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N E S A C S

January 2007 Vol. LXXXV, No. 5

Monthly MeetingJoint Meeting with BAGIM

Chair’s StatementBy Mukund Chorghade

A First-Time MentorNEBHE Science Network by Jin Ji

Summer Research ScholarDesign and Synthesis of Novel Inhibitors of Dihydroorotase

2 The Nucleus January 2007

It is a singular honor and privilege toassume the office of Chair for theNortheastern Section. The breadth,depth and sophistication of the talentand creativity of the individuals in thesection are truly outstanding. We haveeminent researchers and professionalsrepresenting the strategic triad of aca-demia, government and industry fromall sub-disciplines of chemistry. Weenjoy a cherished and hallowed tradi-tion of excellence. The warmth andgracious hospitality with which wewelcome participation by our mem-bers, collaborators and distinguishedguests has been the hallmark of ourtradition and the well-spring of ourprogress

It will be my endeavor to (1) Fos -ter greater interactions between theACS and the other professional bodiescatering to the cause of chemistry -The American Institute of Chemistsand the International Union of Pureand Applied Chemistry come readily tomind. A one-day joint meeting featur-

ing several prominent scientists hasbeen arranged on March 30. This couldbe the forerunner of an annual Life Sci-ences Symposium and could provide auseful forum for productive exchangeof ideas. (2) Encourage a vitalizedspeakers bureau to provide guest lec-tures to schools, universities and civicand community groups. The topics canencompass issues of topical interest,e.g., chemical safety, environmentaland the contributions made bychemists/chemistry to the benefit ofsociety at large. (3) Expand the activi-ties of the Professional Training/Educa-tion and Career Services committees.Regular workshops will be used to edu-cate students at local colleges/universi-ties and mid-career professionals aboutthe diverse opportunities in chemistry,current trends in globalization, resumewriting, interviewing skills/techniquesand related topics. Such workshopswill also benefit mid-career andchemists undergoing a career transi-tion. (4) Build a much-needed bridge

between the medicinal and processchemistry groups and facilitate viasymposia and discussion groups newperspectives on the progress of a drugfrom conception to commercialization.(5) Organize a few lunch time lecturesto attract researchers who, because oftheir busy schedules, are not able toattend the evening lectures. The ACShas novel programs like the sciencecafé’s that will be of great interest toour members. (6) Increase participa-tion of members in the section activi -ties and increase the membership ofthe ACS and the section. This will alsoallow greater opportunities for net-working among chemists. Greateremphasis will be placed on attractingchemists in the biotechnology / bio-pharmaceutical industries and partici-pation of their employers via corporatesponsorships (7) Stimulate additionalparticipation of the section in the inter -national activities of the ACS. Ourmembers are involved in a wide array

2007 Chair’s Statement By Mukund Chorghade

continued on page 16

The Nucleus is distributed to the members of the Northeastern Section of the American Chemical Society, to the secretaries of the Local Sections, and to editors of all local A.C.S. Section publications.Forms close for advertising on the 1st of the month of the preceding issue. Text must be received by theeditor six weeks before the date of issue.Editor: Michael P. Filosa, editor, Ph.D., ZINK Imaging Incorporated, 1265 Main Street,

Waltham, MA 02451 Email: Michael.Filosa(at)zink.com; Tel: 781-386-8479.Associate Editors: Myron S. Simon, 20 Somerset Rd., W. Newton, MA 02465, Tel: 613-332-5273

Nancy Simons, Analytical Chemist, Corporate R&D, Boston Scientific Corp., 1 Boston Scientific Place A4, Natick, MA 01360-1537. Email: Nancy.Simons(at)bsci.com; Tel. 508-650-8603; Fax 508-647-2329Sheila E Rodman, Konarka Techologies Inc., 116 John St. Suite 12, Lowell, MA01852 email:srodman(at)konarka.com tel 978-569-1414

Board of Publications: Mary Mahaney (Chair), Martin Idelson, Vivian K. Walworth Business Manager: Karen Piper, 19 Mill Rd., Harvard, MA 01451, Tel: 978-456-8622Advertising Manager: Vincent J. Gale, P.O. Box 1150, Marshfield, MA 02050,

Tel: 781-837-0424; FAX: 781-837-1453Contributing Editors: Morton Hoffman, Feature Editor; Dennis Sardella, Book Reviews; Calendar Coordinator: Sheila Rodman, email: srodman(at)konarka.comPhotographers: Morton Z. Hoffman and James PhillipsProofreaders: Donald O. Rickter, Myron S. Simon, Vivian K. WalworthWebpage: Webmaster: Sathish Rangarajan, sathish.rangan2(at)gmail.comCopyright 2006, Northeastern Section of the American Chemical Society, Inc.

The Nucleus January 2007 3

The Northeastern Section of the AmericanChemical Society, Inc.Office: Marilou Cashman, 23 Cottage St., Natick, MA 01360. 1-800-872-2054 (Voice or FAX) or 508-653-6329. e-mail: mcash0953(at)aol.comAny Section business may be conducted via the business office above.NESACS Homepage:http://www.NESACS.orgSathish Rangarajan, WebmasterACS Hotline, Washington, D.C.: 1-800-227-5558Officers 2007Chair:Mukund Chorghade14 Carlson Circle, Natick, MA 01360508-651-7809 and 308-3891Chorghade(at)comcast.netChair-Elect:Marietta SwartzChemistry Department, Umass-BostonBoston, MA 02125617-287-6146; marietta.swartz(at)umb.eduImmediate Past Chair:Patricia MabroukChemistry Department, Northeastern UniversityBoston, MA 02115613-373-2845; p.mabrouk(at)neu.eduSecretary:Michael SingerSigma-Aldrich3 Strathmore Rd., Natick, MA 01360508-651-8151X291; msinger(at)sial.comTreasurer:James Piper19 Mill Rd., Harvard, MA 01451978-456-3155, piper28(at)attglobal.netAuditor:Anthony RosnerArchivist:Myron S. Simon20 Somerset Rd.Newton, MA 02465; 617-332-5273Romysimon(at)mindspring.comTrustees:Joseph A. Lima, Esther A. H. Hopkins,Michael E. StremCouncilors Alternate CouncilorsTerm Ends 12/31/2007Thomas R. Gilbert Arlene W. LightMichael J. Hearn Timothy B. FrigoMichael Singer Mary MahaneyPamela Nagafuji Mark FroimowitzTerm Ends 12/31/2008Doris I. Lewis Patrick M. GordonMorton Z. Hoffman Michael P. FilosaChristine Jaworek-Lopes Lawrence ScottMary Burgess Liming ShaoDonald O. Rickter S.B. RajurTerm Ends 12/31/2009Catherine Costello Julia H.MiwaPatricia Mabrouk Alfred ViolaMichaeline F. Chen Wallace J. GleekmanDorothy J. Phillips Eva B. BinnunAmy Tapper Barney Grubbs

All Chairs of standingCommittees, the editor of THE NUCLEUS, and the Trustees of SectionFunds are members of theBoard of Directors. AnyCouncilor of the American Chemical Societyresiding within the section area is an ex officiomember of the Board of Directors.

Contents2007 Chair's Statement _________________________________2By Mukund Chorghade

Grants-In-Aid and Career Services _________________________4

Monthly Meeting _______________________________________5Joint with BAGIM, Yvonne Martin to Speak on "Lessons from 41 Years as aComputational Chemist"

Second Heyn Book Award________________________________6

A First-Time Mentor ____________________________________6NEBHE Science Network by Jin Ji

Report from Seoul _____________________________________7By Morton Z. Hoffman

Summer Research Scholar _______________________________8Design and Synthesis of Novel Inhibitors of Dihydroorotase byKerry Heinzelmann and Evan Kantrowitz

National Chemistry Week Report _________________________10

Connections to Chemistry ______________________________11

Cover: From L-R: Evan Heyn, Mary Mahaney, Chair of the NESACS Board ofPublications, Vincent Gale, Advertising Manager of the Nucleus and recipient ofthe second Arno Heyn Memorial Book Award, Michael P. Filosa, Editor of theNucleus, Vivian Walworth, Board of Publications, Robert Heyn and Janice Heyn.

Deadlines: March 2007 Issue: January 10, 2007April 2007 Issue: February 12, 2007

The Education Committee has awardedGrants-in-Aid of $250 each to fourundergraduates at colleges and univer-sities within the Northeastern Sectionto enable them to attend the ACSNational Meeting in Chicago, Illinoisto present a paper at the Under graduateResearch Poster Session in the Divisionof Chemical Education on Monday,March 27, 2007. Matching funds havebeen committed by the institutions tosupport the students’ travel. The recipi-ents are also required to participate inthe Northeast Student ChemistryResearch Conference (NSCRC) inApril 2007.The awardees, their research supervi-sors, and the titles of the papers are asfollows:Richard Hughes, Jr., Boston College,(Prof. Lawrence Scott) Towards theSynthesis of Arm-Chair Carbon Nan-otubesParesh Agarwal, Massachusetts Insti-tute of Technology (Prof. ChristopherCummins ) An Isolable and MonomericPhosphorous Radical that is Reso-nance-Stabilized by the Vanadium(IV/V) Redox CoupleTaryn Palluccio, Bridgewater StateCollege (Prof. Stephen Waratuke)Hydroaminations of Alkynes, Enynesand Dienes Using Titanium CatalystsChaoyuan Kuang, Massachusetts Insti-tute of Technology (Prof. GrahamWalker) Regulation of Activity of E.coliProteins UmuC and UmuDApplications for the travel stipend areaccepted from students majoring inchemistry, biochemistry, chemical engi-neering, or molecular biology who arein good standing with at least juniorstatus, and are currently engaged inundergraduate research. ◆◆

NESACSCareerServices atMonthlyMeetingsThe NESACS Career Services Com-mittee is dedicated to providing ACSMembers with the best tools to managecareers. We offer career guidance andfocus on the components needed fortargeting the job market: personalassessment, identifying market trends,credentials, research and networking.We have a comprehensive (lecture,demo and review) program that pro-vides assistance in writing winningresumes and cover letters as well asvarious techniques and skills neededfor a successful interview.

In collaboration with the Speaker’sBureau, we will organize a program ofresume reviews and short lecturesfocusing on current topics at SectionMeetings. Two distinguished recruitersin our area, Megan Driscoll and Jen-nifer Sass of PharmaLogics Recruiting,will join me in offering valuable per-spectives and 1:1 career counseling tomembers. These sessions will typicallybe held between 2:30 pm and 4:30 pm.Members will be able to benefit fromsuch networking: this will be a regularfeature of Section Meetings in 2007.

In general our members have pro -vided positive feedback. Reproducedbelow are comments from one memberwho benefited from our programs:“My career counseling session with Dr.Chorghade began with some basicquestions designed to engage me andfocus me on clearly stating my objec -tives. The process of reviewing my CVbegan with an examination of its over -all structure and an assessment of theimpression of prospective screeners.This overview was followed by adetailed review focused on content,wording and vocabulary. I have readseveral books on resume writing and

attended many workshops. The assis-tance that I received through ACScareer services has been the mostknowledgeable and helpful that I haveexperienced. While the improvementsto my CV are significant, the feedbackI received on my qualifications andsearch strategies was profound. Thebest part of the process is the quality ofassistance and sincere caring of thecounselor.” ◆◆


Corporate Patrons and GolfIridiumAstra Zeneca R&D BostonGenzyme Drug Discovery & DevHovioneIBMIRIX PharmaceuticalsJohnson-Matthey Pharma SolutionsLyophilization Service of New Eng-

landMerckPhasex CorporationSepracorStrem Chemicals, Inc.Zone EnterprisesCorporate Sponsors and GolfRhodiumAerodyne Research, Inc.Cambridge Isotope LaboratoriesCambridge Major LaboratoriesNew England BioLabs, Inc.PfizerSigma-RBIShasun Pharma SolutionsDonors and Golf TungstenConsulting Resources Corp.Dishman PharmaceuticalsAnd Chemicals LimitedHoughton Chemical CompanyOrganix, Inc.Vertex

Grants-in-AidAwarded toUnder-graduates

Wallace J.GleekmanThe Editor of the Nucleus is sad-dened to report the death of long-timeNESACS stalwart and retired Brook-line High School teacher , WallyGleekman on November 23, 2006. Amore complete remembrance will bepublished in a future issue. MPF ◆◆

Yvonne Martin retired at the end ofOctober from her position as SeniorResearch Fellow, Volwiler Society,Abbott Laboratories. Her researchinterests include strategies for increas-ing the molecular diversity of com-pound collections; to triage hits fromHTS; to predict the potency, bindingaffinity, or absorption, distribution,metabolism, and excretion (ADME)properties of small molecules fromtheir molecular structures; and for thecomputer design of novel compoundsincluding 3D database searching, denovo design, and pharmacophore map-ping. Dr. Martin did her undergraduatework in chemistry and biology at Car -leton College, Northfield, Minnesotaand her PhD work in chemistry atNorthwestern University focusing onphysical biochemistry. Her entirecareer (40+ years), except for a staywith Corwin Hansch, has been atAbbott Laboratories; the past 35 yearsinvolving various aspects of computer-assisted drug design. She is a memberof the Advisory Board for the QSARand Modeling Society, an editor for thepublication “Perspectives in DrugDesign and Discovery” and a sectioneditor for “QSAR: Annual Reports inComputational Chemistry”. Dr. Martinis on the editorial boards for “TheJournal of Computer Aided MolecularDesign” and “QSAR & CombinatorialScience” and is a former member ofthe NIH Biodata Management andAnalysis Study Section. Honorsreceived include Phi Beta Kappa; NIHpre-doctoral fellow; AAAS fellow;IUPAC fellow; life-time member of theMolecular Graphics and ModelingSociety; and the AccomplishmentAward, The Society for BiomolecularSciences (2005). ◆◆

Biography


Monthly MeetingThe 875th Meeting of the Northeastern Section of the AmericanChemical SocietyJointly with the Boston Area Group for Informatics andModeling (BAGIM)Thursday – January 18, 2007Harvard Faculty Club,20 Quincy St., Cambridge, MA.

2:30 pm Career Services Presentations and Resume Reviews, MukundChorghade, Chair, NESACS; Megan Driscoll and Jennifer Sass ofPharmaLogics Recruiting.

4:30 pm Board Meeting

5:30 pm Social Hour

6:30 pm Dinner

8:00 pm Evening Meeting, Dr. Mukund Chorghade, Chair, presidingDr. Yvonne Connolly Martin, Senior Research Fellow (retired), Volwiler Society, Abbott Laboratories.Lessons from 41 Years as a Computational Chemist

Dinner reservations should be made no later than noon, Thursday, January 11,2007. Please call or fax Marilou Cashman at 800-872-2054 or e-mail atMcash0953(at)aol.com. Please specify vegetarian. Reservations not cancelled atleast 24 hours in advance must be paid. Members, $28; Non-members, $30;Retirees, $15; Students, $10.THE PUBLIC IS INVITEDAnyone who needs special services or transportation, please call Marilou Cash -man a few days in advance so that suitable arrangements can be made. Freeparking in the Broadway St. Garage (3rd level or higher). Enter from Cam -bridge Street via Felton Street.

Career ServicesAre you interested in changing jobs?Do you wonder whether your inter-viewing abilities could be enhanced?Could your resume use some work? Ifyes, please join us at the Januarymeeting, where you can receive advicefrom industry professionals.

Topics and services which we willcover: how to put together an eye-catching resume, best interviewingstrategies, and how to find the mostappropriate opportunities ◆◆

AbstractLessons from 41 Years as aComputational ChemistThis talk will address the followingquestions: how many ways can a com-putational chemist impact the effi-ciency of drug discovery? Do modelsalways have to be accurate to be use-ful? Are there other ways that a com-putational chemist can impact drugdiscovery than by developing or usingquantitative or 3D molecular model-ing? ◆◆


2nd HeynBook AwardPrize toVincent GaleThe second Arno Heyn MemorialBook Prize Award was made to long-time Nucleus Advertising Manager,Vincent Gale. Vince has served theNucleus for sixteen years. He wasrecruited by former Nucleus Editor,Arno Heyn when Arno recreated theNucleus in the form it has today. Vinceis also the advertising manager for anumber of other newsletters publishedby ACS Sections including The Indica-tor, The Vortex, The Catalyst, The Cru-cible, The Del-Chem Bulletin and TheCapital Chemist. Vince also maintainsa website to manage and promoteadvertising in the aforementionedACS sectional newsletters: www.mboservices.net.

The prize was presented at theNovember meeting held at UMASSBoston by Board of Publications mem-ber and long-time friend of Arno Heyn,Vivian Walworth. In attendance fromthe Heyn family were Arno’s sonsEvan and Bob, also present was Bob’swife, Janice Heyn. Last year ’s recipi-ents of the first Arno Heyn Prize wereformer Nucleus editor, Mark Spitlerand former NESACS Webmaster, SamKounaves. MPF ◆◆

Our story begins at the Annual Long-Range Planning Meeting of the North -east Section of American ChemicalSociety (NESACS) back in June of2006. As the new chairperson of theSpeakers Bureau of NESACS and anew board member of NESACS, I wasattending my first Long-Range Plan-ning meeting. The purpose of the meet-ing was twofold: to encouragecommunications among many commit-tees within NESACS, and to stimulatedialogue between NESACS and otherorganizations in the New England area.I wondered to myself, “How will thismeeting impact the Speakers Bureau’sactivities?”

NESACS wanted to establish anactive outreach committee whose goalwas to bridge the chasm betweenchemistry and the public. The out-come: a Speakers Bureau was createdand the NESACS Chair , Dr. PamMabrouk, appointed me its chairpersonstarting in January 2006. The idea wasto organize volunteer speakers, who asexperts and professionals in chemistryfields could speak to schools, indus-tries and different communities andorganizations about the benefits of ourprofession. The events would be freeto the audience. Six months into build-ing the bureau, the bureau hadattracted twelve passionate profession-als and willing speakers. We had evenplanned a series of career counselingevents at monthly NESACS meetingsstarting in September. But what else?

At the Long-Range Planningmeeting, besides the board membersthat I often saw at regular monthlyboard meetings, I noticed a few newfaces. One of them was Emorcia Hillfrom New England Board of HigherEducation (NEBHE). She discussedan annual event that NEBHE wasorganizing – the Science Network atMIT on November 18th, 2006 which isan event to introduce college and highschool students who are interested insciences and technologies to peers andto inspiring mentors in these fields.

Emorcia described how much impactand guidance the events in the past hadoffered to the students. She als ostressed that with more and more stu-dents attending the event each year,NEBHE was constantly looking forqualified experts and professionals inthese fields to be inspiring mentors.

“That’s interesting!” I thought tomyself, “Introducing students to thepossibilities of a career in chemistry orchemistry-related sciences is exactlywhat our Speakers Bureau should bedoing! That’s something we definitelyshould take part in.” After Emorciaspoke, I introduced myself and wedecided to discuss further the collabo-rations between our two organizations.

The planning went smoothly. Isent out a solicitation within the bureauand three speakers, MukundChorghade, Robert Litman andMichael Filosa, responded with posi-tive feedback. They were all enthusias-tic about becoming advisors for theevent. Susan Bryant, the coordinatorof the event, was very appreciative ofSpeakers Bureau’s participation andmentioned that NEBHE hoped “to con-tinue working with the SpeakersBureau in the future.”

Saturday, November 18th, 2006,would be an interesting day for themany students and mentors who partic-ipated in the Science Network at MIT– and a delightful day for Robert Lit -man, Michael Filosa and myself whohad the honor of representing thebureau. The event was full of youngcurious minds, lots of energy and anabundance of excitement when it cameto learning about careers in science,technology and engineering. They hadendless questions.

All the mentors and advisors weredivided into dif ferent groups andmatched with students who have spe -cific interests in their fields. Havingbeen working in biochemical fieldsand developing medical devices, I wasassigned to be a mentor for a group of

A First-Time MentorBy Jin Ji, PhD Chairperson, Speakers Bureau of NESACS


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The 19th International Conference onChemical Education (ICCE) was heldon August 12-17, 2006, at SookmyungWomen’s University in Seoul, Korea.Attracting almost 400 participantsfrom 36 nations around the world,including more than 20 from theUnited States, the conference, whichhad as its theme, Chemistry and Chem-istry Education for Humanity, wasorganized by a committee headed byConference Chairman Jung-Il Jin andOrganizing Committee ChairmanChoon Do. Welcoming remarks weremade by Eun Lee, President of theKorean Chemical Society, which co-sponsored (with IUPAC) the confer-ence as part of its 60th anniversarycelebration and recognition of 2006 asthe “Year of Chemistry” as declared bythe government of the Republic ofKorea.

The conference featured a numberof very distinguished chemists andeducators as plenary lecturers: BassamShakhashiri (USA), Enlightenment,The Responsibilities of the Enlight-ened, and Exhor tations for GoodTeaching; Nobel Laureate AaronCiechanover (Israel), The UbiquitinProteolytic System: From Basic Mech-anisms Through Human Diseases andonto Drug Targeting; Su-Moon Park(Korea), Chemistry Education forMore Chemistry Majors; ACS Presi-dent Ann Nalley (USA), Applicationsof Computer Molecular Modeling inTeaching Organic Chemistry; Onno DeJong (The Netherlands), MakingChemistry Meaningful: Conditions forImproving Context-Based ChemistryEducation; Viktor Obendrauf (Aus-tria), More Small-Scale Hands-onExperiments for Easier Teaching andLearning; Peter Atkins (UK), TheChallenge of Education. A chemistrydemonstration presentation by DavidKatz (USA), Chemical PrinciplesVisualized, and a forum on Young

Ambassadors for Chemistry(YAC):Past and Future led by Lida Schoen(Netherlands) were also part of thehighlighted program.

After the welcoming reception onSaturday evening, the sessions beganon Sunday morning with symposia onthe public understanding of chemistry,the role of chemists, inorganic chem-istry, multimedia and visualization,how students learn, and teacher educa -tion. During the next days, other sym -posia were presented on women andchemistry; green chemistry; general,analytical, organic, polymer, environ-mental, computational, forensic, andphysical chemistry and material sci-ence; networking and accreditation ofchemistry and chemical engineeringeducation; microscale laboratory tech-niques; web-based teaching and learn-ing arts in chemical education future of

textbooks; instructional strategies;experiments and demonstrations;gifted learners. In total, more than 300presentations were made, including120 posters, many of which wereoffered by elementary, middle, andhigh school teachers. Details of theprogram are available on the ICCE2006 website: http://www.19icce.org/.

One outstanding part of the meet -ing program was the exhibit of postersby school children on the theme, Chem-istry for Humanity, which was organ-ized by “Science Across the World,”the IUPAC Committee on ChemistryEducation (CCE), and the KoreanChemical Society. An initial group of945 entries from 32 countries had beenwinnowed down to 13 posters (age10-13) and 41 posters (age14-16) for pres-entation at ICCE. A jury, consistingLida Schoen (Netherlands), Eva

REPORT FROM SEOULMorton Z. Hoffman, Boston University <[email protected]>U.S. National Representative to the IUPAC Committee on Chemistry Education and ACS Division of Chemical Education Liaison to IUPAC

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Continued on page 11


Dihydroorotase (DHOase) is the second enzyme in pyrimi -dine nucleotide metabolism; it catalyzes the reversible ringclosure of N-carbamoyl-L-aspartate (CA) to form dihy-droorotate (DHO).

DHOase is a member of the amidohydrolase superfam -ily of enzymes. The mechanism of the enzymes in thissuperfamily involve Zn2+ ions.1 In mammals, DHOase ispart of the multifunctional enzyme CAD along with aspar -tate transcarbamoylase and carbamoyl phosphate synthetase,but in bacteria DHOase is an independent enzyme.2 Thestructure of homodimeric E. coli DHOase has been deter-mined, and the active site was shown to contain two Zn 2+

ions.3 In the determined structure one active site containsCA and the other contains DHO (see Figure 1).

The DHO from the malaria parasite ( P. falciparum) andE. coli DHOase have 27.5% conserved residues, includingall residues involved in catalysis and metal binding. Thissuggests that the active site structure of P. falciparumDHOase is similar to the structure of E. coli DHOase, andthat their catalytic mechanisms are the same. Seymour etal.4 have shown that an inhibitor of DHOase results in theaccumulation of carbamoyl aspartate and an overalldecrease in the formation of pyrimidine nucleotides. There-

fore, since P. falciparum does not have a salvage pathwayfor pyrimidine nucleotides, inhibitors of P. falciparumDHOase have the potential to have anti-malarial activity.

The active site of DHOase was found to be a pocketwithin a pocket. When DHO binds to the enzyme, it bindsto the lower pocket, adjacent to the Zn 2+ ions, leaving thehydrophobic upper pocket empty. Because the upper pocketremains empty, a potential inhibitor of DHOase may bind tothis upper pocket, or it may expand off of the substrate tofill the upper pocket. A virtual screening system developedin the Kantrowitz lab was used to identify potentialinhibitors of DHOase by docking a library of compounds tothe active site with and without DHO bound. Identifiedcompounds were evaluated kinetically and used to designsecond generation inhibitors.ResultsIdentification of possible DHOase inhibitors

As a means to identify an entirely new classes ofinhibitors we used a virtual screening that allows for therapid evaluation of interactions between an enzyme activesite and small molecule compounds. This was accomplishedcomputationally using available docking programs. Optimization of virtual screening for DHOase

Because of the different algorithms used, a specificdocking program may be better suited for a particular tar getactive site. Therefore, we tested three programs to see whichwould be the best for DHOase. The three programs testedwere AUTODOCK3,5 DOCK56 and SURFLEX.7

Program optimization was performed on DHOase withthe substrate carbamoyl aspartate bound in one active siteand the product DHO bound in the other (PDB entry 1J79 3).The molecule in the active site was removed and its coordi -nates changed so that it was in a dif ferent spatial position,unrelated to the actual binding site. The DHO or CA wasthen docked into the active site using AUTODOCK3,DOCK5 and SURFLEX. The RMS deviation between theDHO from the X-ray structure and the best conformer fromAUTODOCK3 was 0.36 Å, 0.49 Å for DOCK5 and 3.5 Åfor SURFLEX. The large RMS deviation with SURFLEXwas due to its inability to position the carboxylate in theproper orientation. Therefore AUTODOCK3 was selected tobe used to identify new inhibitors (see below)Identification of new inhibitors of DHOase by vHTS

All of the compounds in the Sigma-Aldrich catalogwere docked to the DHO site in DHOase usingAUTODOCK3. The two compounds that gave the bestresults from the docking were 1 and 2.

Summer ScholarDesign and Synthesis of Novel Inhibitors of Dihydroorotaseby Kerry Heinzelmann, Advisor: Evan Kantrowitz, Boston CollegeDepartment of Chemistry, Merkert Chemistry Center, Chestnut Hill, MA 02467

Figure 1. Structure of homodimeric E. coli DHOase (PDB entry 1J79).The structure of each monomer is organized as a “TIM” barrel. The prod-uct DHO is shown in the right active site, while the substrate CA is shownin the left active site. The two Zn2+ ions in each active site are also shown.

continued on page 9


Ability of 1 and 2 to inhibit DHOase 1 and 2 were tested for their ability to inhibit DHOase.

Reactions were setup at sub-saturating concentrations ofDHO, and in the absence and presence of increasing con -centrations of either 1 or 2. As seen in Figure 2, 1 was notable to inhibit DHOase over the concentration range tested,while 2 exhibited significant inhibition.

Modifications to the structure of 2

Modifications of 2 were docked in order to optimize theinhibitory effects on DHOase. Molecules with differentbase units (3, 4, 5) were examined, with the R groups repre -senting different cyclic amines and then docked to checktheir respective affinity for the active site. The base unitmost like the substrate, 2-oxohexahydropyrimidine-4,6-dicarboxylic acid, 3, was selected for the synthesis of thefirst set of compounds. Compound 3 was not commerciallyavailable, however its synthesis had been previouslyreported.8 Problems occurred during the synthesis of 3

including consistently low yields of the desired oxidationproduct, and formation of undesirable side products.Because of the problems with the synthesis of 3, structurallysimilar compounds that were commercially available andshowed binding affinity for the enzyme were considered asbase units instead. We are currently using one such com-pound, 1,3,5-cyclohexanetricarboxylic acid 4, as a base unitfor synthesis of potential inhibitors. As seen in Figure 3,two of the carboxylic acids of 4 are initially benzyl pro-tected using 2 equivalents of benzyl alcohol. An amine isthen coupled to the unprotected carboxylic acid in the pres -ence of DCC, HOBt, and Et 3N. Finally, after the two acidgroups are deprotected by catalytic hydrogenation, anotheramine can be coupled to one acid group by using the samecoupling conditions. (e) Future directions

This project is being continued during the current aca -demic year as part of an undergraduate research project.Currently, a series of molecules with compound 4 as theirbase unit are being synthesized. AUTODOCK was used tohelp select the R groups that would enhance binding toDHOase. Once these syntheses are complete, the com-pounds will be assayed to determine their ability to inhibitDHOase. In the future, we plan on synthesizing compoundswith 1,3,5-benzenetricarboxylic acid 5 as the base unit, andcomparing the inhibition of these compounds to those con -taining 4. Experimental ProcedureEnzyme purification

The plasmid that contained the gene for E. coliDHOase (obtain from Frank Raushel, Texas A&M Univer-sity) was transformed into a special E. coli strain that can beinduced to produce T7 polymerase. The strain/plasmid com-bination was grown in YT media at 37°C until the A600reached 0.6, at which time 0.4 mM IPTG was added toinduce the production of the enzyme. After overnightgrowth, the cells were harvested by centrifugation followedby sonication to break open the cells. Ammonium sulfatewas added to the clarified lysate to 60% saturation. The pre-cipitate, containing the protein, was dissolved in buf fer (50mM Tris-phosphate, 100 µM ZnCl2), then dialyzed againstthe same buffer. Anion-exchange chromatography was thenused to purify the DHOase using Source Q resin (GE Heath-

Figure 2. Inhibition of DHOase by inhibitors 1 (circles) and 2 (squares).

Compounds 1 and 2

Compounds 3, 4 and 5

Figure 3. Synthesis using the 1,3,5-cyclohexanetricarboxylic acid, 4, baseunit. (a) CDI, Benzyl alcohol, rt 24 h; (b, d) DCC, HOBt and Et3N; (c)10% Pd/C, CH3OH, 18 h.


Summer ScholarContinued from page 8


Care). The column was eluted with agradient of NaCl in the above buffer.Fractions containing enzyme werecombined and checked for purify bySDS-gel electrophoresis.Enzyme activity determination

The activity of the DHOase in theabsence and presence of inhibitors wasdetermined by measuring the initial rateof the reaction in the reverse direction.The amount of N-carbamoyl-L-aspar-tate formed was determined colorimet-rically as previously reported.9

References1. Nam, S. H.; Park, H. S.; Kim, H. S. Evo -

lutionary relationship and application ofa superfamily of cyclic amidohydrolaseenzymes. Chem Rec 2005, 5, 298-307.

2. Lee, L.; Kelly, R. E.; Pastra-Landis, S.C.; Evans, D. R. Oligomeric structure ofthe multifunctional protein CAD that ini-tiates pyrimidine biosynthesis in mam-malian cells. Proc Natl Acad Sci U S A1985, 82, 6802-6.

3. Thoden, J. B.; Phillips, G. N., Jr.; Neal,T. M.; Raushel, F. M.; Holden, H. M.Molecular structure of dihydroorotase: a

paradigm for catalysis through the use ofa binuclear metal center. Biochemistry2001, 40, 6989-97.

4. Seymour, K. K.; Lyons, S. D.; Phillips,L.; Rieckmann, K. H.; Christopherson,R. I. Cytotoxic effects of inhibitors of denovo pyrimidine biosynthesis upon Plas-modium falciparum. Biochemistry 1994,33, 5268-74.

5. Goodsell, D. S.; Morris, G. M.; Olson,A. J. Automated docking of flexible lig-ands: applications of AutoDock. J MolRecognit 1996, 9, 1-5.

6. Shoichet, B. K.; Bodian, D. L.; Kuntz, I.D. Molecular docking using shapedescriptors. J. Comp. Chem. 1992, 13,380-397.

7. Jain, A. N. Surflex: fully automatic flexi-ble molecular docking using a molecularsimilarity-based search engine. J MedChem 2003, 46, 499-511.

8. Adams, J. L.; Meek, T. D.; Mong, S. M.;Johnson, R. K.; Metcalf, B. W. cis-4-Carboxy-6-(mercaptomethyl)-3,4,5,6-tetrahydropyrimidin-2(1 H)-one, a potentinhibitor of mammalian dihydroorotase.J Med Chem 1988, 31, 1355-9.

9. Pastra-Landis, S. C.; Foote, J.;Kantrowitz, E. R. An improved colori-metric assay for aspartate and ornithinetranscarbamylases. Anal. Biochem. 1981,118, 358-363. ◆◆

Summer ScholarContinued from page 9 National

ChemistryWeek Report By Christine Jaworek-LopesApproximately 3000 individualslearned about NCW through the eventsheld this year. The breakdown was asfollows: ~450 individuals attended thekick-off event at Wellesley College,~1500 individuals visited the Chil-dren’s Museum and ~1000 individualsvisited the MOS on October 28, 2006.Over 100 volunteers from 12 differentorganizations (ACS members, PhyllisA. Brauner Memorial Committee,Emmanuel College, Gordon College,Malden High School, Mass GeneralHospital, Merck Chemical Company,Northeastern University, SimmonsCollege, Suffolk University, Tufts Uni-versity, Wellesley College) contributedto the successful week.

The NCW committee would liketo offer Salutes to Excellence Awardsto the following: Merck ChemicalCompany for financial support of theevents as well as providing all thematerials for the chromatographydemonstration performed at the MOS-Boston, Boston Children’s Museum,Museum of Science-Boston , andWellesley College.

As of November 14, 2006, onlytwo puzzle solutions and no posterswere submitted as part of the contest.

NCW 2007 will be from October21 – October 27, 2007. The theme is“The Many Faces of Chemistry .” Thekick-off event on October 21 will beheld at the Museum of Science as wellas an outreach event on October 22. Athird event will be held at the Chil-dren’s Museum on October 27. ◆◆

Åkesson (Sweden), Margaret-AnnArmour (Canada), Peter Atkins (U.K.),Karl Brachtl (Austria), Marianne Cutler(UK), Morton Hoffman (USA), OnnoDe Jong (Netherlands), MordechaiLivneh (Israel), Jim McQuillan (NewZealand), Mauro Mocerino (Australia),and Kay Stephenson (UK), chose thewinning posters in the two age cate-gories. The winners received certifi-cates of recognition and smallelectronic devices as gifts.

Social activities associated withthe conference included a visit to theKorean Folk Village, preceded bylunch in a traditional Korean familyroadside restaurant (leaving shoes atthe door, seating on mats on the floor,following the colorimetric rule forspiciness [the redder the food, the hot -ter it is]); Participants’ Night withnational songs and performances; anda banquet in a high-rise building with astriking view along the Hangang Riverwith entertainment by an ensemble ofsingers and instrumentalists perform-ing Korean classical-modern “fusion”music on traditional instruments.

The ICCE was the occasion of theannual meeting of the CCE. Chairedby Peter Mahaffy (Canada), the com-mittee consists of eight titular mem-bers, eight divisional representatives,and 19 national representatives. TheCommittee approved the minutes of itsmeeting in Beijing in August 2005,received the minutes of the CCE strat -egy meeting in Puerto Rico earlier in2006, and reports from the followingsubcommittees: Development of Mate-rials for Raising Awareness about theChemical Weapons Convention; PublicUnderstanding of Chemistry; Chem-istry for Development; MicroscaleGroup; DIDAC (development ofdidactic tools). CCE received anupdate on the Bologna process inEurope and the development of theEuroBachelor degree in chemistry.CCE will meet next in Torino, Italy, onthe occasion of the IUPAC GeneralAssembly and Congress, August 4-12,2007, Chemistry Protecting Health,Natural Environment and Cultural

Heritage <www.iupac2007.org>.The 20th ICCE will be held on

August 3-8, 2008, in Pointe auxPiments, Mauritius. The theme of theconference will be Chemistry in theInformation and Communications

Technologies; see http://www.uom.ac.mu/20icce.htmfor more information.This article is taken from ChemistryInternational, Vol. 29, No. 1 (Jan.2007) by permission. ◆◆

Report from SeoulContinued from page 7


The Connections to Chemistry programtook place at Burlington High School(Burlington, MA) on Wednesday, Octo-ber 18th, 2006, 3:30 –8:00 PM. Eachregistrant participated in two of thefive different workshops that werescheduled including a workshop onengineering in chemistry, a NationalChemistry Week workshop on paintsand coatings, and a workshop on start-ing a high school chemistry club, oneof the new initiatives of the EducationDivision of the ACS. Terri Taylor, theManager of the ACS Office of HighSchool Chemistry in Washington wel-come the participants on behalf of theAmerican Chemical Society at theopening meeting and also gave theworkshop on high school chemistry

clubs. (Her office donated 150 of thecanvas CHED bags for the programfrom the BCCE program held at Pur-due University this past summer.) Dr.Daniel Nocera, Professor of Chemistryand W. M. Keck Professor of Energy atthe Massachusetts Institute of Technol-ogy gave a very spirited eveningaddress: The Energy Future of OurPlanet which was followed by a raffleof American Chemical Society items(mugs and laser pen pointers), sub-scriptions to the Journal of ChemicalEducation (2 of which, were donatedby the Journal) memberships in CHED(donated by CHED), and membershipsin CTC (Chemistry Teacher Connec-tion). ◆◆

Connections to ChemistryBy Ruth Tanner


THE SPEAKERS BUREAU OF NESACSBRIDGING THE CHASM BETWEEN SCIENCE AND THE PUBLIC

CALL US IF:YOU ARE CONSIDERING having a speaker toengage your group in a lively and healthy discussion on scientific topics of current interest.

YOU ARE knowledgeable in chemistry or related sciences and passionate about sharing your valuable knowledge with curious audiences.

Mission StatementThe Speakers Bureau of NESACS (Northeastern Section of the AmericanChemical Society) acts as a bridge between the public and science. Weare a group of qualified volunteer speakers who have in depth knowledgein chemistry and related sciences and are passionate about sharing ourprofession with the public. We use intrigue, analogies and humor toinform the public about new strides in sciences, build awareness of sci -ence and and confront the misconceptions about our profession withknowledgeable answers

Contact Marilou Cashman at [email protected] , or Dr. Jin Ji, Chairperson ofthe Speakers Bureau at [email protected] , or go to www.nesacs.org/sb/home.htmlfor more information.

How does our volunteer, free-of-charge program work? Step 1. We find out what the publicwants to know by communicating withvarious organizations such as museums,schools, and neighborhood groups.

Step 2. We set up speaking eventsthrough these public venues at no char geto your organization or your audience.

Step 3. One of our knowledgeable speak-ers presents a scientific topic of interestand engages in a healthy discussion.

(l-r) Doris Lewis (Suffolk University), Bassam, Susan Brauner, Hyacinth Brauner. Photos by Morton Z. Hoffman

Professor Bassam Z. Shakhashiri, candidate for ACSPresident, during his presentation of the Phyllis A.Brauner Memorial Lecture at Wellesley College onOctober 22, 2006.

Brauner Memorial Lecture October 22, 2006


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Please check NESACS websiteand university websites for latebreaking changes. Jan 17Milton R. Smith, III (Michigan State Univ.) “TBA.”(Woodward Lecture Series, Harvard-MITInorganic Chemistry Seminar.)MIT, Room 6-120, 4:00 p.m.

Jan 22Jeffery Kelly (The Scripps Research Institute)“TBA”(Woodward Lecture Series, Organic ChemistrySeminar)Harvard Univer, Pfizer Lecture Hall 4:15 p.m.

Jan 23 Prof. Anne Gershenson (Brandeis Univ.)“Single Molecule Studies of MolecularMousetraps: Serpin Folding & ProteaseInhibition” Boston College, Merkert 130 4:00 PM

Jan 24Dr. William Reiff, (Northeastern Univ.)“TBA”Northeastern Univ. Hurtig Hall Rm 129 12 Noon

Jan 30 Prof Gregory Petsko (Brandeis Univ.)“Structural Neurology: A New Approach to theUnderstanding, Treatment and Prevention ofNeurodegenerative Diseases”Boston College, Merkert 130 4:00 PM

Jan. 31 Dr. Elena Rybak-Akimova (Tufts Univ.),“TBA”UMass Dartmouth;Building Group II, Room 115 4:00 PM

All notices for the Calendarshould be sent to Sheila RodmanKonarka Technologies, Inc.116 John St., Suite 12Lowell, MA 01852srodman (at) Konarka.com

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Calendarof activities here-the collaboration withthe German Chemical Society has beenoutstanding! Plans are well under wayfor extensive collaboration with theIndian and the Chinese Chemical Soci -eties. One of ACS’s most successfulmechanisms for delivering highlyfocused technical content in the UnitedStates has been through the ProSpec-tives series of conferences. The presti-gious “ProSpectives” conference willbe organized at various locations inIndia and China.

So, dear members, please join us inwhat promises to be an outstanding yearof progress and additional programs.Volunteers like you are a tremendoussource of ideas that constitute thelifeblood of an organization. Join acommittee of your choice, provide cre -ative inputs into the programs and joinus in increasing the public’s awarenessand enjoyment of Chemistry. ◆◆

Chair’s StatementContinued from page 2

students who had interests in medicalfields. This was an utterly new experi -ence for me as I have always consid-ered myself a learner and constantlyidentified people in my professionalcareers as my own mentors.

Many of the students in my grouponly knew how to get into medicalfields through premedical studies andMedical school. Once they found outthat I majored in chemistry and wasworking at Harvard Medical Schooldeveloping medical devices, they beganprobing for details: “How did you getto where you are today?”, “Were thereany obstacles?”, “How did you knowthis was what you wanted to do?”…

It made me think. I must haveasked similar questions when search-ing for a path for my life. I must stillbe asking these questions in my heart,or out loud, but not realizing it. Theanswers to these questions are helpfulto the people who asked the questions,also those who through their heartsanswered the questions. It was a dayreflecting as well as advising. It was aday in which so many promising stu-dents learned about us, our work and,their future. ◆◆

A First-Time MentorContinued from page 6

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