medicinal chemistry exam 1

1

Medicinal Chemistry 410 Exam #1 February 29, 2008 Name: Med. Chem. #

Part I. (75 Points) There are 50 multiple choice questions worth 1.5 points each (75 Points). Please use the Scantron Sheet provided.

1. The anticancer drug illustrated below:

NH2

NH2

PtO

O

O

OH

H

I reacts with DNA primarily forming an interstrand cross link. II exhibits greater nephrotoxicity than cisplatin. III primarily forms adducts with a single strand of helical DNA.

a I only b III only c I and II only d II and III only e I, II, and III Answer

2. The drug illustrated below:

SO

ONH

H2NN O

CH3

I is a false substrate that mimics p-aminobenzoic acid. II inhibits the De Novo synthesis of folates in bacteria.

III is used to treat bacterial urinary tract infections (UTI’s). a. I only b. III only c. 1 and II only d. II and III only e. I, II, and III Answer

3. The drug illustrated below has which of the following properties:

NO

CH3

H

H

HN

O

NOCH3C CH3C

NS

H2N

SO3

NaO

O

I is recognized for its effectiveness against gram (-) bacteria II cross allergenicity in patents sensitive to pencillins is fully expected. III is used orally.

a I only b III only c I and II only d II and III only

e I, II, and III Answer

2


N

N N

N

NH2

OPO

HOOH

I is associated with chain termination in the synthesis of viral DNA. II is converted to a mimic of 2’-deoxyadenosine triphosphate. III is resistant in viruses with a deficiency in viral thymidine kinase.



N CH2CH2CH2C

Cl

ClO

OH

I is too unstable for oral administration. II primarily cross-links two individual DNA strands. III is a bifunctional alkylating agent.



NO

NH

HO

S

CO2

CH2

H

NO

NS

H2N

N

CH3H3C COOH

I is NOT orally active. II is β-lactamase resistant. III inhibits bacterial cell wall synthesis by inhibiting penicillin binding protein ( a transpeptidase).



I. is a potent antifungal agent. II binds to the heme portion of a specific cytochrome P450. III is an aromatase inhibitor.


3


NN

O

OH3CH2C OH

OO

H2CCH3

N

N

O

I is a mitotic spindle poison. II is a substrate for the efflux transporters MDR1 and BCRP. III stabilizes the cleaved complex formed from topoisomerase I and DNA.



NN

NH2

NH2H2C

H3CO OCH3

OCH3

I inhibits dihydrofolate reductase in bacteria. II irreversibly inhibits the enzyme thymidylate synthetase. III blocks protein synthesis by binding to ribosomal RNA.



I blocks androgenic receptors. II has been used to treat prostate cancer. III inhibits 5α-reductase, the enzyme which reduces testosterone to 5α-dihydrotestosterone.



N

N

NN

O HCH3

I is used in monotherapy (single-agent therapy) of HIV infection. II is NOT cross-resistant with nucleoside reverse transcriptase inhibitors. III is a non-competitive inhibitor of reverse transcriptase.


4

12. The drug illustrated below: I is leucovorin and is used in “rescue therapy”. II inhibits DNA synthesis by limiting the DeNovo synthesis of thymidine. III inhibits dihydofolate reductase.



NO

NH

HO

S

CCH2OCONH2

H

N

O

O

O CH3

CH3O

OOCH3

I is a prodrug. II is β-lactamase resistant. III can be administered orally.



CH2CH3

OCH2CH2NCH3

CH3

I has been used to prevent breast cancer in high risk individuals. II is an estrogen receptor antagonist. III inhibits the synthesis of estrogen.



N

N

OO

S

NH2

HOH2CH H

I is used in combination with the thymidine mimic, Zidovudine (AZT). II does cause chain termination of developing viral DNA. III is effective against RNA-containing viruses.


5


NHP

O O

N(CH2CH2Cl)2

I can only be administered intravenously. II is a bifunctional alkylating agent. III is associated with hemorrhagic cystitis.


17. The drug illustrated below is:

OH OHOH

O

NH2

O

OH

N(CH3)2HHO CH3

O

H I is a bacterial protein synthesis inhibitor. II is active orally. III is β-lactamase resistant.



HOH

H

H

OHC CH

CH3 I is an oral contraceptive. II is an estrogenic steroid. III has a 11β-hydroxyl group.



I does NOT require oxidative metabolism, but only hydrolysis to be active. II can cause hemorrhagic cystitis as a side effect. III is a bifunctional alkylating agent.


6


HN

NH

OF

O

I is converted to its 2’-deoxyribosylmonophosphate. II ultimately can irreversibly bind to and inhibit thymidylate synthetase. III is associated with photosensitivity.



N

OCO2H

N

F

OCH3N

H

H

H

I initially blocks protein synthesis in bacteria. II has inhibitory activity on bacterial cell wall synthesis. III targets the enzyme DNA gyrase and converts it into a cellular poison.



NH

CH3

H

H H

CH3H

O

HNO

CH3C

CH3

CH3

H

I has been used to treat hair loss (alopecia) in males. II has been used to treat benign prostatic hyperplasia. III acts as a competitive inhibitor 5α-reductase activity.



CH2NHNHCH3(H3C)2HCHNCO I is used to treat tuberculosis.

II is a monofunctional alkylating agent. III requires metabolic activation.


7


O

N N

O

NNH

O

Cl

CF3

H3C

H H

I is a protein tyrosine kinase inhibitor. II is used to treat hepatocellular carcinoma. III targets Raf kinase, PDGF, c-Kit, and VEGFR (-2 & -3).



I is activated to an inhibitor of dihydrofolate reductase. II is used in combination therapy to prevent the parasitic disease, malariaIII stimulates L-asparaginase in cancer therapy.



CH

H

H H

CH3H

O

O

OH

HO

O

I a potent mineralocorticoid. II has an 11β-hydroxyl group. III among the more potent glucocorticoids.



OCH3

CH2OH

O

OH

O

OH3C

OHNH2

O

O OH

I acts by targeting topoisomerase II. II is known to exhibit cardiac toxicity. III extravasation of this agent is associated with severe necrosis at the site of infusion.


8


HN

N N

N

OO

O

H2N

CONH2

CH(CH3)2H

CH2OH

I is a 2’deoxycytosine mimic. II is a prodrug. III requires phosphorylation by viral thymidine kinase for activity.



C NCH2CH2ClClH2CH2CNO

H N O

I is associated with nausea and vomiting. II is transformed into two different monofunctional alkylating agents. III is used to treat brain tumors



NN

N

F

F

OHN

N

N

I binds to ergosterol and disrupts the cell membrane of fungi II is used systemically. III inhibits 14α-demethylase in the biosynthesis of ergosterol.



I is a non-nucleoside reverse transcriptase inhibitor. II is a HIV protease inhibtor. III acts as a “transition state” enzyme inhibitor.


9


N

S

O

CH3

CH2

COOH

H O O

N NN

I a highly effective Gram (-) antibiotic. II orally active. III a β-lactamase inhibitor.


33. Bevacizumab, Avastin®

I is an antibody that binds to the receptor for vascular endothelial growth factor. II is a humanized monoclonal antibody. III prevents the vascularization (endothelial cell growth) that is associated with tumor growth



N

NC O

H

N

HOCH2CH3

CO2CH3

H

N

H

CH2CH3

OCOCH3

OHCO2CO3

H

I is lethal if administered by intrathecal injection. II acts as a mitotic spindle poison by destabilizing microtubules and promoting their dissolution. III acts as a mitotic spindle poison by inhibiting the disassembly of microtubules.



I is a suicide substrate. II is a non-competitive and an irreversible inhibitor. III an antagonist for the aromatase receptor associated with stimulating estrogenic activity in mammalian breast tumor cells.


10

36. The drug illustrated below

HN

N N

N

OHOH

O

I ultimately acts as a guanosine mimic. II is incorporated into viral DNA. III is synergistic with AZT (a thymidine mimic).



O

N

CH3

CH3

CH3

CH3O

H3C

H3CH3C

HO

CH3CH2

HOO

O

OH3C

OH

OCH3

CH3

CH3

NCH3H3C

O

I has limited clinical use because of its short half-life. II cannot form the ketal intermediate at low pH that is associated with the stomach cramping of other macrolide antibiotics. III is not cross allergenic with penicillin antibiotics.


38.

Acute Lymphocytic Leukemia (ALL)

I is uncontrolled growth of B- or T-lymphocytes. II is the most common of childhood leukemia III is the uncontrolled growth of granulocytes.



OHCH3

H

HHHO

OH

I is a metabolite of estrogen. II is used to increase fertility. III is the second most potent androgenic metabolite of testosterone.


11


H2N NS

PO

OHHOH

I used to prevent hemorrhagic cystitis associated with the administration of cyclophosphoramide. II activated by alkaline phosphatase. III used to prevent renal toxicity associated with the administration of cisplatin.



I has an anabolic:androgenic ratio of 3:1. II is an orally active synthetic estrogen. III is an aromatase inhibitor.



CH3

CH3HOH

F H

O

O

O

O

O

O

I Is a potent glucocorticoid. II Is a potent mineralocorticoid. III Is used as an abortifacient.


43. The drug illustrated below: Rituximab, Rutuxin®

I is a monoclonal antibody used to treat metastatic breast cancers that overexpresses human epidermal growth factor 2, HER2. II acts as an antiangiogenic agent to prevent the production of new blood vessels. III is used in the treatment of non-Hodgkin’s lymphoma that possess the membrane bound phosphoprotein, CD-20.


12


CH2HS CH2 SO

OO

Na

I converted to its disulfide in the kidney and then rapidly eliminated in urine. II used to prevent hemorrhagic cystitis that is commonly associated with the administration of cyclophosphoramide. III rapidly converted to its disulfide in the bloodstream.



C C CCH3

CH3CH3

NCH3

I inhibits squalene epoxidase in the synthesis of ergosterol. II cannot be used orally, but is effective topically for Tinea infections. III inhibits 14α-demethylase in the biosynthesis of ergosterol.



CH3

CH3CH3

OH

HO

CH3H3CCO

CH3H3CO

O

O

O

O

O

NH

N N N CH3

OHH3C

CH3

O

O

I binds to ergosterol producing an antifungal effect. II known to induce cytochrome P450 enzymes, such as CYP450 3A4. III Binds to mycobacterial DNA dependent RNA polymerase.



OH OHOH

O

NH2

O

OH

N(CH3)2HHO CH3

O

H

I rarely is associated with allergies. II can discolor and retard growth of developing teeth in children. III can be administered orally.


13


N

N N

N

NH

H2N

HOH2C

I is used in combination with nucleoside reverse transcriptase inhibitors that mimic thymidine or 2’-deoxycytosine. II must be converted to a 5’-triphosphate to be active. III is metabolically converted to a mimic of 2’-deoxyguanosine.



I is an orally active peptide. II is a gonadotropin-releasing hormone agonists (GnRH) III is used to treat advanced prostate cancer.

a I only b III only c I and II only d II and III only e I, II, and III Answer 50. The drug illustrated below:

I binds to CCR5 and prevents interaction with gp120 acting as a chemokine receptor antagonist. II is orally active. III is an entry inhibitor preventing HIV entry into non-infected human T cells.


Part 2 Generic Names (9 Points). Provide the Generic Names for the Compounds listed on the following page. In the space provided under the structure of each the compounds illustrated, write the correct CAPITALIZED letter corresponding to the choice of answers given on the bottom of the page. The letter “Z” may be used as an answer as seldom or as often as needed.

14

SO

ONH

H2NN

N

OCH3H3CO

Answer

N

OCO2H

NN

H3C

F

O CH3H

Answer

OHCH3

H

H HO

CH3

Answer

OH OHOH

O

NH2

O

OH

N(CH3)2HH CH3

O

H

HOH

Answer

NO

COOH

HH3C

HOH S

H

NH

H

ON

CH3

CH3H

CH3H

Answer

N N CH2H CH CH3

NN

O

OH

O

O

Answer

S

NH3C

H3C

N

O

N

CH3H3C

O

N N

O

O

N

S

CH3 H

H

OH H

Answer

NO

NH

HO

S

CO2

CH2OCCH3

H

NOCH3

NS

H2N

O

NaAnswer

Answer

Answer

O

O

H2NH2C

NH2

H2N

O

NH2

OOH

H2N

HO

HO

HOHOCH2

6'

Answer

Answer

Answer

C C CCH3

CH3CH3

NCH3

Answer

N

S

O

NH

HCH3

CH3

COOH

O

CH

HO

H2N

H

Answer

NN

FCH3

N

NN

F

F

OH

Answer

N

N

O

O

CH3H

O

N3

HO

CH3

N

Answer

OHCH3

H

HO

C C

H3C

CH3

Answer

A. Cefotaxime J. Mifepristone S. Dacarbazine B. Etoposide K. Testosterone T. Dexrazone C. Clavulanic acid L. Amoxicillin U. Aldosterone D. Doxycycline M. Zidovudine V. Piperacillin E. Betamethazone N. Finasteride W. Levofloxacin F. Topotecan O. Meropenem X. Ritonavir G. Tobramycin P. Trimethoprim Y. Voriconazole H. Terbinafine Q. Ribavirin Z. None of These I. Sulfadoxine R. Oseltamivir

15

Part 3 Nomenclature 16 Points. When using the basic templates provided insert all unsaturation as required and specify the orientation of all functionality or hydrogen atoms by using BOLD lines/wedges or HASHED lines/wedges. Example

CH3

H

OR

H3C

H

NOT

CH3

H 1. Pregna-1,4-diene-3,20-dione, 11β-hydroxy-6α-methyl [known as Endrysone]

2. 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[amino(2-

bromophenyl)acetyl]amino]-8-oxo-3-(1-propenyl)-, [6S-[6α,7β(S*)]]-

16

3. 6H-Purine-6-one, 2-amino-1,9-dihydro-1-ethyl-9-[2-hydroxy-1-(fluoromethyl)ethoxy]methyl

4. 3-Quinoline carboxylic acid, 6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-7-(1-

piperazinyl)-, monohydrochloride [known as Sarafloxacin]

N Exam Total: Part 1. Multiple Choice 75 Points

Part 2. Generic Names 9 Points

Part 3 Nomenclature 16 Points

Total

medicinal chemistry exam 1

Documents

mitotic spindle poison

bifunctional alkylating agent

viral thymidine kinase

prevent hemorrhagic cystitis

hemorrhagic cystitis

viral dna

potent mineralocorticoid

uncontrolled growth