journal of medicinal chemistry volume 21 issue 6 1978 [doi 10.1021%2fjm00204a013] hansch, corwin;...

8/18/2019 Journal of Medicinal Chemistry Volume 21 Issue 6 1978 [Doi 10.1021%2Fjm00204a013] Hansch, Corwin; Hathewa…

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574 Jou rna l of Medicinal Chemistry, 1978, Vol. 21, No. 6

(13) (a ) Y. T. Lin, T. L. Loo,

S.

Vadlam udi, and A. Goldin, J .

Med . Chem., 15, 201 (1972); (b) W.

J.

Dunn 111, M. J.

Greenberg, and S.

S.

Callejas, ibid., 19, 1299 (1976).

(14) H. Druckrey, Xenobiotica,

3,

271 (1973).

(15) D. D. Bed, J. L. Ski bba , W. A. Croft, S. M. Cohen, and

G.

(16) D. J. Thompson, J. A. Molello, R. J. Strebing, and I. L. Dyke,

(17)

T.

M. Ong and F. J. De Serres, M ut at . Res., 20, 17 (1973).

18) E. Vogel, R. Fahrig, and G. Obe, Mu ta t. Res., 21,12 3 (1973).

(19) R.

Suss,

U. Kinzel, and

J.

D. Scribner, “Cance r”, Spring-

20)

C. Hansch, S.

H.

Unger, and A. B. Forsythe, J . Med. Chem.,

T. Bryan,

J .

Na tl. Cancer Inst. , 54, 951 (1975).

Toxicol. Appl. Pharmacol. , 33, 281 (1975).

er-Verlag, New Yo rk, N.Y., 197 3, p p 49-52.

H ansch e t a l .

16, 1217 (1973).

(21)

S.

L. Edwards, J.

S.

Sherfinski, and R. E. Marsh,

J .

Am.

Chem. SO C., 6, 2593 (1974).

(22) C. Hansch, R. N. Smith, and R. Engle in “Pharmacological

Basis of Cancer Chemotherapy”, Williams and Wilkins,

Baltimo re, Md., 1975, p 231.

(23) V. A. Levin, D. Crafts, C. B. Wilson, P. Kapra, C. Hansch,

E. Boldrey,

J.

En ot, and M. Neely, Cancer Chemother. Rep.,

59, 327 (1975).

(24) All new compounds prepared in the Pomona Laboratory

were tested in CDF mice by the NCI, qdl-9, using Klucel

as the vehicle. DTI C was used as a positive control; see

R.

I.

Geran, N. H. Greenberg,

M. M.

Macdonald, A. M.

Schumach er, and B. J. Abbott, Cancer Ch emother. Rep.,

3 (no. 2) (1972).

25) C. Hansch and T. Fujita, J . Am. C hem. SOC., 6,1616 (1964).

(26) G.

F.

Kolar and R. Preussmann,

2

Naturforsch. B, 26,950

(1971).

(27)

T.

Fujita,

J.

Iwasa, and C. Hansch,

J .

Am. Chem. SOC.,6,

5175 (1964).

(28) W. Haggerty, Midwest Research Institu te, unpublished

results.

(29) A. Leo, C. Hansch, an d D. Elkins, C hem. Rev., 71,525 (1971).

(30) C. Hansch, A. Leo, S. H. Unger, K. H. Kim, D. Nikaitani,

and E . J. Lien, J . Med. Chem ., 16, 1207 (1973).

(31) C. Hansch,

S.

D. Rockwell, P.

Y.

C. Jow,

A.

Leo, and E . E.

Steller, J . Med. Chem., 20, 304 (1977).

(32) A. Leo, P.

Y.

C. Jow, C. Silipo, and C. Hansch, J . Med.

Chem., 18, 865 (1975).

(33) C. Hansch, G.

J.

Hatheway,

F.

R. Quinn , and N. Greenberg,

J . Med . Chem ., following pape r in this issue.

Antitumor l-(X-Aryl)-3,3-dialkyltriazenes.. On the Role of Correlation Analysis

in Decision Making in Drug Modification. Toxicity Quantitative

Structure-Activity Relationships

of

l-(X-Phenyl)-3,3-dialkyltriazenesn Mice1

C o r w i n H a n s c h , * G e r a r d

J.

H a t h e w a y ,

Dep artm ent of Chem istry, Pomona College, Claremont, California 91 711

Frank R. Q u i n n ,

Laboratory of Medicinal Ch emistry and Biology, Developmental Therapeutics Program, Division of Cancer Trea tme nt,

National Cancer Ins t i tute , National Ins t i tutes of Health, Bethesda, Maryland

20014

and N a t h a n i e l G r e e n b e rg

Drug Evalu ation Branch, Developmental Therapeutics Program, Division of Cancer Treat men t, Nati ona l Cancer Ins titu te,

National Ins t i tutes of Health, Bethesda, Maryland 20014. Received Sep tember 23,

1977

A series of

11

triaze nes (X-C6H,N=NNRCH,) was char acter ized for toxicity in mice

(LD,,).

The quanti ta t ive

structure-activity relationship (QSAR) obtained for toxicity was comp ared with th e QSAR for antitum or activity.

Th e close correspondence of the two QSAR leaves essentially no means for th e synthe sis of more p oten t, less toxic

triazenes.

In the pr evious paper in th i s s e rie s, 2 eq 1

was

f or mula ted

l og 1 / C =

0.10

logP -

0.04

( l o g

P)’

-

0.31

E:*

-

0.18

MR-2 6

0.39

E -R 4.12

1)

=

61; r

=

0.836;s

= 0 . 1 9 1 ;

logPo

= 1.18

f o r t h e a n t i t u m o r a c t i v i t y of X-C6H4N=N-NR1R2 ac t ing

a g a i n s t

L E 1 0

l e u k e m i a i n m i ce .

C

i n e q

1

s t h e c o n -

c e n t r a t i o n ( m o l e s per ki logr am) pr oduc ing a T / C of 140,

MR-2,6

is the sum of

molar

r e f ra c t i v it y o f s u b s t i t u e n t s i n

the

two ortho

pos i t ions , and

E,-R

i s t h e T a f t s t e r ic pa-

r amete r f or the larger of

R1 and

Rz.

The

log Po of 1.18sets

the u p p e r l i m i t o f p o t e n c y w h i c h can be o b t a i n e d i n t h i s

s e r i e s b y m a n i p u l a t i o n o f

the

l i p o p h i l i c / h y d r o p h i l i c

ba lance . Essent ia l ly the same log Po was f o u n d f o r i m -

idazolyl- and pyrazolyl tr iazenes .2

The

o n l y a d v a n t a g e t o

be g a i n e d f r o m the MR-2,6 t e r m i s o b t a i n e d w h e n

both

0022-2623

,I

81 1821-0574$01.00/0

o r t h o p o s i ti o n s

are

u n s u b s t i t u t e d . For pr ac t ica l pur poses ,

t h e E,-R

te rm

l i m i t s o n e t o t h e N ( C H & s i nc e NHCHB

c o m p o u n d s a r e so unstable.

A t f i r s t g l a n c e , o n e

presumes that

m o r e a c t i v it y c o u l d

be o bta ined by in t r oduc ing mor e e lec t ron- re leas ing gr oups

( large negative Zu’); however, the

QSAR

of eq 2 effectively

log k x / k ,

= -4 .42

-

0.16

=

14;

r = 0.995; s = 0.171

l i m i t s t h i s a v e n u e .

E q u a t i o n 2 c o r r e l a t e s t h e r a t e o f

hydr o lys i s o f phenyl t r i azenes .2 Th is i s

so

e n o r m o u s l y

p r o m o t e d b y e l e c t r o n - r e l e a s i n g g r o u p s

that

i t i s not

poss ib le in pr ac t ice to go beyond th e 4- O CH 3 ( hal f -l i fe =

1 2 m i n ) i n the use of e lec t r on- r e leas ing f unc t ions .

At-

t e m p t s to i n c r e a s e p o t e n c y t h r o u g h s t e r i c a n d / o r h y -

dr ogen- bonding e f f ec t s o f o r tho subs t i tuen ts have r eached

978 American Chemical Society


2/4

Ant i tumor 1

X-Aryl ) -3 ,3 -d ia lkyl t r iazenes .

2

Table I. Constants for LD,, vs. Rats of

X-C,H,N= N-N(CH,),

115

log

og

1 c

X Obsd Calcdb l/Cl LogPC

u

4-NO, 2.06

2 . 15 0 . 09

2 . 7 1 0 . 7 9

H 2.54

2 . 4 9 0.05

2 . 5 9 0.00

4-CH3 2.62

2 . 7 4 0 . 1 2

2 . 9 3 - 0 . 3 1

4-I 2.68

2 . 75 0 . 07

3 . 7 0 0 . 1 4

4-C1 2.71

2 . 65 0 . 06

3 . 3 3 0 . 1 1

4- F 2 . 71

2 . 5 5 0 . 1 6

2 . 67 -0 . 07

4-OCH, 2 . 7 2 2 . 7 8 0 . 0 6 2 . 30 -0 . 78

4-Br 2.73

2 . 68

0 . 0 6

3 . 4 8 0 . 1 5

calculated using eq 7 in ref 2 except for the experimen-

tally determined value for the unsubstituted compound.

a From ref 3. Calculated using eq 4.

Log P values

Table 11.

Constants for LD,, vs. Mice of

H

IA log

og 1 / c

R Obsd Calcdb l /C l L og P

Methyl 2.44

2 . 4 1 0 . 0 3 - 0 . 2 4

Ethy l 2 . 75

2 . 6 3 0 . 1 2

0 . 7 6

Propyl 2.70 2 . 86 0 . 16

1 . 7 6

Butyl 2 .91 3 . 08 0 . 17

2 . 1 6

Pentyl 3.49

3 . 3 1 0 . 1 8 3 . 7 6

a From ref 4.

Calculated using eq 5.

the point where no obvious opportunities present them-

selves for exploitation.

T he single remaining ro ute to more effective triazenes

appeared to be th at of decreasing their toxicity and thereby

obtainin g congeners with better therapeutic ratios. Th e

purpos e of this re port is to consider th is possibility.

Tw o previous studies3v4 f toxicity of triazenes hav e been

reporte d; however, both suffer seriously from a poor se-

lection of derivatives. We have formulate d eq

3-5

from

LD r a t s of X - C 6 H 4 N = N N ( C H 3 ) 2 Tab le I )

log

1/C

-0 .355 k0.36)

U +

+

2.60

k0.15)

= 8; =

0.698 ;

s =

0.175;

Fl x=

5.71

log

1 / C

=

-0 .47 k0 .27)

U*

0.29 k0.24)

l o g P

n = 8; r =

0.906 ;

s

= 0.113; , , x =

9.22

LD mice4 of

[x

( Tab le 11)

l o g

1/C 0.23 k0.19)

l o g P

2.46 k0.42)

n

= 5 ;

r

=

0.912; s

=

0.185;

F , , x =

19.8

the da ta presented in these two s tudies . Th e data upon

which eq

3

an d

4

rest (Table

I)

contain a good spread in

u

of substituents but a poor spread in log P values.

Equat ion

3

indicates that the electronic term is most

impo rtant. Th e confidence limits on the log P term in eq

4

are broad so th at we cannot place much confidence in

this term. Adding a term in (log P 2 oes not improve

things. About all tha t one can conclude from eq 3 and 4

is tha t electron-releasing groups increase toxicity a nd t ha t

u

gives a slightly bette r correlation th an

u,

suggesting a

role for through resonance. T he results with the imida-

zolyltriazenes (Table

11)

are also of little value because of

the confidence limits on the log P te rm and the few data

points.

We have now determined the LD50 values for 11 phe-

3 )

1 .75 k0 .73) 4 )

CONH2

N = N N ( R ) 2

H

5)

Journal

of

Medicinal C hemistr y, 1978, Vol. 21, No. 6

575

Scheme I

/ microsomal

C,H.N=N-N

\

oxidation

C,H,N= NN

-+ C , H , N = N N H CH ,O

\

proximal

W O H ca rcin ogen

H l O

CH: [HO N=N CH ,] C,H,NH, ,H,NHN =NC H,

nyltriazenes. In this set of

11

congeners, we have included

compo unds with a wide range of log P values (0.98-4.70),

as well as a good sprea d in u values

(-0.78 t o 0.66).

Results

Equat ions 6 an d 7 have been derived from the d ata in

log 1/C - 0.0283 k0.02) ( log

P ) 2

n

=

;

r = 0.731 ; s = 0.174; F1,x = 10.31

log

1/C

=

0.0241 k0 .013)

( log

P ) 2

-

7 )

=

11;

r =

0.913;

s = 0 110; , 9 x=

14.3

Table 111 on the LD50 of phenyltriazenes for mice.

Equat ion 7 is a significant improvement over the best

single-variable equation, eq 6

F1,9;u=0.01

10.6;

F1,8;u=0.01

=

11.3). Subs t i tu t ing

u

for

u

gives the same quality

correlation

r = 0.910).

Adding

a

term in log

P

to eq

7

does

not afford a significant reduction in the variance. C n

the se equations is the concentration producing th e LD,.

Log Po represents the ideal Iipophilicity for the most toxic

compound; since its value is 0, making congeners eith er

more or less lipophilic would reduce their toxicity in terms

of th e LD,; however, because of the sma ll coefficient with

this t erm , significant changes are afforded only by large

changes in log P. For example, substitu ting log P of 6 in

eq 7 (with

u =

0) yields log 1/C

=

2.6; substituting log

P of 6 in eq 1 (with

u =

0, MR-2,6

= 0.2,

E,-R

=

-1.24)

yields log 1 / C of 2.7; therefore, the therapeutic ratio is 1.04.

Doing the same with log P of 1 (ideal log P for potency)

yields a thera peu tic ratio of 0.95;hence, there is virtually

nothing to be gained therapeutically by the manipulation

of log P. Furthermore, not only do the

u+

terms of eq 1

and 7 cancel each other as far as th e thera peutic index is

concerned but, in addition, eq 2 tells us that trying to

increase potency by using substituents more electron

releasing than 4-OCH3 will simply produce drugs too

unstab le with which to work. All path s appear to be

blocked to bette r drugs in th is series.

Discussion

In order t o assess more clearly what remains to be done,

it behooves us a t this point in our analysis to take a

broader view of the w ork which has been done with tr i-

azenes. Although th e antitum or activity of the triazenes

was discovered5 in

1955

and a large am oun t of work has

been done with these substances in the pas t

2

years, the

mechanism of their antitumor action is still poorly un-

derstood. Since the triazenes ar e also carcinogenic, a

considerable effort has been m ade to establish how they

react in mammals.

Preus sma nn an d his colleagues6 mad e one of the first

3.483 k0 .18) 6)

0.264 k0.16)

u

3.490 k0.12)


3/4

576

Journal of Medicinal Chemis try ,

1978,

Vol. 21 No. 6

Hansch e t

al .

Table 111.

Cons tan ts for LD,, of X-C,H,N=NNCH,R vs. CD F, Mice

IA log

og

1/c

X R Obsd Calcd

1/c

Log P

U

NSC no.

4 - N H C ( = O ) N H 2

CH3 3.68 3 .63 0 .05

1 . 2 5

4- O CH 3

CH3 3.5 5 3.57 0.0 2 2.30'

4-CONH,

C,H,

3 .46 3 .25 0.21 2.46

3 .43 3 .33

0.10 2.59

3.32 3.36

0.04 1 . 2 0

3 .26

3.37 0.11 2.93'

3.24 3 .33

0 .09 1 .70

3.20

3 .18 0 .02 2 .39

3.05

3 .00 0 .05 3 .6ga

2.80

2.87

0 .07 4 .70

H CH3

4-CONH2 CH,

4-CH3 CH3

4- CO N H 2 C*H ,

4- SO 2N H , CH , 3 .20 3 .32 0 .12 0 .98

4-CN CH3

4-CF3 CH,

4 - C O N H 2 C P , ,

DTIC 2.68 -0.24

' og P calculated us ing techn iques and eq

7

in ref 2.

Table IV. Activi ty against L1210 Leukemia

Dose, Activity NSC

C o m p d m g / k g V / C ) n o .

1

1 2 7 5 2 3 7 1

O.J,,N=N~(C~H '*

3 2 1 4 5 7 5 9 4 7

c

KCHb

2 5 0 126 4 0 6 8 0 1

N= U

CH3 N = N N m O

20

1 2 4 1 2 3 1 5 1

WCH,

NINN(C2H512

4 5 0 1 4 1 1 3 6 0 7 4

studies of the action of microsomes on the simple phe-

nyltriazene I. They postulated t he following mechanism

I

for the generation of carbonium ions which they con sidered

to be the carcinogenic agent (Scheme I). Th ey also

suggested that the monomethyltr iazene is the actual

proximal carcinogen.

They showed that, under their

experimental conditions, HN (CH 3)2was not dealkylated

by microsomes and the benzene diazonium ion was not

reduced to aniline; this was interp reted to mean th at any

C6H 6N2 + roduced via hydrolysis is not the active carci-

nogen. Th eir belief tha t CH3+ is the active moiety is

supported by the findings that triazenes alkylate DNA and

RNA in vitro and in vivo to produce 7-m ethylguanine and

other methylated nucleic acid bases. ̂ ^ C6H5N=N-NH-

C2H6produces 7-ethylguanine. An impor tant difference

between carcinogenicity and antitumor action of the

triazenes is that C 6H 5N= NN (C2H ,), is carcinogenic but

-0.69

- 0 .78

0 .36

0.00

0.36

- 0 .31

0.36

0.57

0.66

0.61

0.36

2 6 8 4 9 2

5 1 5 4 6 0

8 7 4 2 9

3 0 9 4

8 6 4 4 1

4 8 8 2 1

2 7 6 3 7 5

1 5 7 0 3 0

1 5 7 034

1 5 7 0 3 3

2 7 6 7 4 1

4 5 3 8 8

has been reported as having no antitumor activity

(however, see below). Th is suggests tha t Schem e I may

not be the m echanism responsible for antitumo r activity.

Another confusing finding of Preu ssm ann an d Hengy6

is that dealkylation occurred with liver or lung microsomes

bu t not with brain or kidney microsomes; yet triazenes do

not cause liver or lung cancer but do produce brain and

kidney tumors. They suggested tha t the intermediates

[ C 6 H5 N=NN( C H3 ) C H2 0 H o r C 6 H5 N=NNHC H3 ] a r e

produced in the liver and the n transpo rted to other parts

of the body where they decompose to produce carbonium

ions. The y found tha t the half-life of C6H5N=N NHC H3

a t p H 7.4 and 37 C in the presence of serum is 6 min;

while this m ight explain tum ors in other p arts of the body,

it is indeed strange tha t liver tumors a re not found. Since

triazenes alkylate guanine, it may be tha t guanine, in some

stage of D NA synthesis, is more exposed to alkylation t han

in liver tissue.

Pitt i l lo et ala9 ound th at in bacterial cells, DTIC

[4-

(3,3-dimethyl-l-triazeno imidazole-5-carboxamide]s more

effective in inhibiting dividing cells than resting cells (>56

to 1). In this respect

it

differs from alkylating agen ts such

as nitrogen mustards, which are only three times as ef-

fective against dividing cells, and C1CH2CH2N(NO)CO-

NHCH ,CH,Cl, which is only 13 tim es more effective

against dividing cells. Again, the evidence points ou t that

triazenes do n ot behave as ypical alkylating agents in their

antitum or activity.

Geru lath e t al.1° have stud ied the effect of DT IC with

reference to the phases of the cell cycle in Chinese ham ster

ovary cells in vitro. Th ey conclude tha t DT IC kills cells

most effectively in t he G1 an d early S phase and tha t

it

is only moderately lethal to cells in other p hases of the cell

cycle. Thi s evidence in mammalian cells also supports a

different mode of action of DTIC from typical alkylating

agents.

Hrad ec and Kolar'l have shown th at various triazenes

promote t he formulation of aminoacyl-tRNA in cell-free

systems. Th is was also found for other carcinogens.

A recent report by Connors e t al.12 suggests tha t th e fact

that substituents in the phenyltr iazene series may be

strongly electron releasing or withdrawing has little or no

effect on antitumor activity of phenyltriazenes acting

against TL X 5 lymphoma. Th is, of course, is not in line

with our findings on

L1210

leukemia or Dunn et al.13

findings on Sarcom a

180

tumor. In addition to noting that

the electronic effect of ring substituents had no effect on

antitumor activity, Connors et al. concluded, as others

have, tha t an NC H3 group is essential for activity. Data

in Table IV from th e N ational Cancer Ins ti tute indicate

tha t this point is not yet sett led.

Another conclusion of Connors et al. is that when

a


4/4

Ant i tum or 1- X-Aryl) -3,3-dialkyl tr iazenes . 2

methyl group and a larger alkyl group are on the 3-nitrogen

atom , the larger alkyl group is more rapidly dealkylated.

Th eir own work shows th at N (E & is dealkylated only half

as f ast a s N(C H3) 2. McMahon’s work,14 which has been

treated in QSAR terms,15 shows t ha t N-dem ethylation

occurs in preference t o dealkylation of larger alkyl groups.

If

the larger group were always dealkylated more rapidly,

the n one might surmise th at t he biologically active species

is the C H3+ fragment; the results in T able IV do n ot

suppor t th is .

In sum mar y, we can say that neither t he mechanism of

ant itum or activity nor the m echanism of carcinogenicity

of the triazenes is well understood; however, there is no

doubt that these compounds are both quite toxic in a

nons pecific model (LD50) an d highly carcinogenic. Since

we have not been able to separ ate the structura l features

for toxicity from those for efficacy, there is little supp ort

to encourage further work on triazenes

as

antitumor agents.

Dunn13 has also concluded t ha t “...the separatio n of toxic

and antitum or activities would be difficult...” on the basis

of two QSAR, one for efficacy and one for LD5o.

One mig ht argue that m ost of our evidence in sup por t

of discontinuing work on triazenes comes from the X-

C6H4N=NN< series and that exploration of aromatic

heterocycles m ight uncover new leads. While there is no

absolute way to refute this argum ent, the

QSAR

for py-

razolyl- and imidazolyltriazenes2does not suggest any leads

in this direction. In addition, Hutchinson16has shown that,

as far as increased survival time in mice is concerned,

DTIC, C6H5N=NN(CH,), , and C6H5N =NNH CH3 all

gave the sam e increase in life span, although ab out three

times as much D TIC was needed. Thi s follows from its

suboptimal log

P

and t he relatively greate r electronega-

tivity of the imidazole ring compared with the phenyl ring.

The important element is the electronic factor s ince

phenyltr iazene has a superop timal log P value.

Since there a re almost an infinite number of conceivable

aryltriazenes, it is impossible to s tate now, or even after

several thousand more congeners have been made and

tested, tha t a better derivative cannot be found. However,

it is our belief tha t there a re many much more interesting

lead compounds for antitum or activity in which it would

be more profitable to invest one’s resources. Unless one

had new biochemical or molecular biological information

suggesting that a new triazene might be more effective in

some specific way, we would not recomm end the synthesis

and testing of new congeners.

Journal of Medicinal Chemistry, 1978,

Vol.

21 No. 577

Method

Th e log P values and u constants used in this study are

the same as those in paper 1 n this series.2

Th e drug adm inistra tion regimen for determination of

LDWvalues consisted of daily injections on days 1-9.17 Th e

LDWvalues were calculated by plotting percent mortality

vs. log dose utilizing th e pr obit method.I8

References and Notes

1) This research was suppo rted by the F. J. Robbins Research

Fun d a nd by C ontract N01-CM-67062 from t he Division of

Cancer Treatment, National Cancer Institute, National

Institutes of Health.

(2) G.

J.

Hatheway, C. Hansch, K. H. Kim,

S.

R. Mils tein, C.

L.

Schmidt, and R. N. Smith, J .

Med. Chem. ,

preceding

paper in this issue.

(3)

0.

AndrgsovB,

V.

Rambousek, J. Jirl sek , V. Zeveiina, M.

Matrka, and J. Marhold,

Physiol. Bohemoslou.,

21 ,63 (1972).

(4) K. Hano,

A.

Akashi,

I.

Yamamoto,

S.

Narumi, and H. Iwata,

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journal of medicinal chemistry volume 21 issue 6 1978 [doi 10.1021%2fjm00204a013] hansch, corwin;...

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