Anthracycline Antibiotics - American Chemical Society


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Chapter 9 Synthesis a n d Study of Structure—Activity Relationships of New Classes of Anthracyclines

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Antonino Suarato, Francesco Angelucci, Alberto Bargiotti, Michele Caruso, Daniela Faiardi, Laura Capolongo, Cristina Geroni, Marina Ripamonti, and Maria Grandi Pharmacia-Farmitalia Carlo Erba, R & D Oncology—Immunology, 20159 Milan, Italy

Structure-activity studies in the f i e l d of anthracyclines have been very fruitful in defining those moieties that are necessary to produce derivatives active on MDR tumor c e l l s . We have found that substitutions on the sugar part of anthracyclines are fundamental to confer a c t i v i t y on MDR cells in v i t r o . In particular, compounds substituted at C-3' of the sugar moiety with 4-morpholino group or selected potential alkylating moieties are able to overcome resistance both in vitro and in vivo. O v e r t h e l a s t 20 y e a r s , t h e a n t h r a c y c l i n e s d a u n o r u b i c i n 1 and d o x o r u b i c i n 2 h a v e p r o v e d t o b e e f f e c t i v e a n t i c a n c e r a g e n t s f o r t h e management o f h e m a t o l o g i c m a l i g n a n c i e s a n d a l a r g e v a r i e t y o f s o l i d tumors.

Doxorubicin, i n p a r t i c u l a r , i s c u r r e n t l y the f i r s t drug o f c h o i c e f o r t h e t r e a t m e n t o f many tumor t y p e s . A m a j o r 0097-6156/95/0574-0142$08.00/0 © 1995 American Chemical Society Priebe; Anthracycline Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

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l i m i t a t i o n i n the c l i n i c a l use of a n t h r a c y c l i n e s however i s the development of r e s i s t a n c e i n chemosensitive tumors f o l l o w i n g a s u c c e s s f u l i n i t i a l response (1-3). Tumor c e l l s r e s i s t a n t to a n t h r a c y c l i n e s e x h i b i t i n most cases the c l a s s i c a l multidrug r e s i s t a n t (MDR) phenotype. MDR cells are r e s i s t a n t to s e v e r a l c l a s s e s of drugs because they have h i g h l e v e l s of a membrane g l y c o p r o t e i n , pl70, that i s able to recognize and expel the c r o s s - r e s i s t a n t compounds, t h e r e f o r e preventing the drug from reaching c y t o t o x i c i n t r a c e l l u l a r concentrations (4,5). As a consequence, an important pharmacological target i n the s y n t h e s i s of novel anthracyclines is the identification of chemical modifications capable of conferring a c t i v i t y against resistant cells. In t h i s framework, the search f o r molecules a c t i v e on r e s i s t a n t tumors has been one of our major o b j e c t i v e s i n the area of new a n t h r a c y c l i n e research. In order to i d e n t i f y new molecules that might not be recognized by pl70, we have synthesized s e v e r a l c l a s s e s of new compounds m o d i f i e d on the aglycone, modified on the sugar r e s i d u e , and m o d i f i e d on both. The i n v i t r o c y t o t o x i c a c t i v i t y of a l l molecules we synthesized was evaluated using a human colon adenocarcinoma c e l l l i n e , LoVo (6), and i t s d o x o r u b i c i n r e s i s t a n t s u b l i n e , LoVo/DX (7). The c y t o t o x i c a c t i v i t y i s r e p o r t e d as IC , the concentration i n h i b i t i n g 50% of colony formation, c a l c u l a t e d on concentration response curves. The r e s i s t a n c e index (R.I.) i s the r a t i o between the I C on r e s i s t a n t c e l l s and the IC on s e n s i t i v e c e l l s . The i n v i v o a c t i v i t y was evaluated u s i n g disseminated P388 murine leukemia (10 cell/mouse t r a n s p l a n t e d i v i n CD2F1 mice)(8) and i t s doxorubicin-resistant subline, P388/DX (10 cell/mouse t r a n s p l a n t e d i v i n BD2F1 m i c e ) ( 9 ) . Treatment with drug was given i v one day a f t e r tumor t r a n s p l a n t a t i o n . The antitumor a c t i v i t y of the drug was evaluated by comparing the median s u r v i v a l time (MST) of the t r e a t e d group with that of the c o n t r o l group, and the r e s u l t s were expressed as %T/C, where: 50

50

50

6

5

%T/C

= (MST of t r e a t e d group)/(MST of c o n t r o l group) χ

Both LoVo/DX and P388/DX c e l l s e x h i b i t the mdr A n t h r a c y c l i n e s Modified on the

100

phenotype.

Sugar Moiety

The aminosugar is a critical determinant for the pharmacological and biochemical a c t i v i t y of daunorubicin and d o x o r u b i c i n . The b a s i c amino group at C-3' confers water s o l u b i l i t y to the a n t h r a c y c l i n e s and i s i m p l i c a t e d i n determining the DNA a f f i n i t y b i n d i n g (10) . I t i s noteworthy that chemical m o d i f i c a t i o n s on the sugar p a r t of anthra­ c y c l i n e s may a f f e c t t h e i r hydrophobic behavior, and i n most cases, the a b i l i t y to overcome MDR i s r e l a t e d to the

Priebe; Anthracycline Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

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144

ANTHRACYCLINE

ANTIBIOTICS

i n c r e a s e d l i p o p h i l i c i t y of the compounds and consequently to t h e i r a b i l i t y to q u i c k l y enter c e l l s and reach c y t o t o x i c i n t r a c e l l u l a r l e v e l s (11) . A n t h r a c y c l i n e s modified on the sugar moiety have been prepared e i t h e r by condensing the aglycone w i t h novel s y n t h e t i c sugars or by c h e m i c a l l y modifying daunosamine aminosugar. So f a r , a l a r g e number of such d e r i v a t i v e s have been d e s c r i b e d i n the s c i e n t i f i c and patent l i t e r a t u r e (12) . Of p a r t i c u l a r i n t e r e s t among these are c l a s s e s of compounds i n which the amino group at C-3 ' has been p l a c e d at C-4' s i t e , and the C-3' s u b s t i t u t e d w i t h a hydrogen atom or hydroxy group. 4'-Amino-anthracyclines were prepared e i t h e r by s y n t h e t i c manipulation or by s y n t h e s i s of aminosugars and subsequent condensation w i t h aglycônes. Of p a r t i c u l a r s y n t h e t i c i n t e r e s t was the s p l i t t i n g of the C-3'-amino of 4'-epidaunorubicin 3 via aziridino intermediate 4, whose regiochemical opening gave 3'hydroxy-4'-amino a n t h r a c y c l i n e g l y c o s i d e 5, the aminosugar i n xylo c o n f i g u r a t i o n . I n v e r s i o n of the 3 *-hydroxy group afforded isodauno 6, which was converted to the corresponding C-14-hydroxy d e r i v a t i v e 7 (13) .

Ο

OH

Ο

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Similarily, xylo anthracycline glycoside 8 was converted, v i a a z i r i d i n o intermediate 9 , i n t o g l y c o s i d e 1 0 w i t h an arabino c o n f i g u r a t i o n (14).

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HO

8

9

1

0

3 •-Deamino-4 '-amino a n t h r a c y c l i n e s 1 1 and 1 2 were prepared r e s p e c t i v e l y from 5 and 1 0 upon s u b s t i t u t i o n of 3'-hydroxy group w i t h i o d i n e atom and subsequent r a d i c a l displacement (15) .

1

The c l a s s of 4 -aminoanthracyclines i s endowed w i t h i n t e r e s t i n g antitumor a c t i v i t y , p a r t i c u l a r l y compound 7 (Isodoxo), which showed remarkable antitumor a c t i v i t y both on leukemia and s o l i d tumors and was found t o be l e s s c a r d i o t o x i c than doxorubicin (16,17). These b i o l o g i c a l f i n d i n g s prompted us to i n v e s t i g a t e a l t e r n a t i v e ways t o s y n t h e s i z e 4-aminosugars, i n order t o prepare analogues w i t h d i f f e r e n t aglycones and to study t h e i r activity a g a i n s t MDR c e l l s . S t a r t i n g from L-rhamnal 1 3 , 2,4,6trideoxy-4-amino-L-lyxo-exo-pyranose 1 4 , 2,4, 6-tri-deoxy-4amino-L-arajbino-exopyranose 15, 2,3,4,6-tetra-deoxy-4amino-L-threo-exopyranose 1 6 and 2,3,4,6-tetra-deoxy-4amino-L-erythro-exopyranose 1 7 were prepared (12) . These aminosugars, p r o t e c t e d as t r i f l u o r o a c e t a t e at the

13

2

14:R = OH 15:R = H

16:R = OH 17:R = H

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ANTHRACYCLINE ANTIBIOTICS

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amino a n d h y d r o x y g r o u p s , were c o n v e r t e d i n t o 1-chloro d e r i v a t i v e s and condensed w i t h s y n t h e t i c a g l y c o n e s t o p r o d u c e d i f f e r e n t c l a s s e s o f a n t h r a c y l i n e s . Among t h e s e , t h e most i n t e r e s t i n g compound was 4-demethoxy-3'-deamino4'-deoxy-4·epiaminodaunorubicin 1 8 , d e r i v e d b y c o n d e n s i n g 4-demethoxydaunomycinone with the 1-chloro-Nt r i f l u o r o a c e t y l d e r i v a t i v e o f aminosugar 1 7 ( 1 5 ) .

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04demDn

Ο

OH

Ο

The c y t o t o x i c a c t i v i t y o f 4'-amino a n t h r a c y c l i n e s i n comparison w i t h doxorubicin i s reported i n Table I . Compounds 7 a n d 1 0 b e a r i n g t h e h y d r o x y g r o u p a t p o s i t i o n C-3' do n o t e x h i b i t i m p r o v e d a c t i v i t y a g a i n s t LoVo/Dx c e l l s , a s shown b y t h e i r r e s p e c t i v e R . I . v a l u e s o f 21.8 a n d 27.5. Conversely, 4 '-amino d e r i v a t i v e s 1 1 , 1 2 , 1 8 a r e a c t i v e o n LoVo/DX c e l l s , w i t h R . I . v a l u e s o f 2.6, 9, 0.9, r e s p e c t i v e l y . Compounds 1 2 a n d 1 8 , i n w h i c h t h e amino g r o u p is a t p o s i t i o n 4 ' - e q u a t o r i a l , have i n c r e a s e d potency a g a i n s t b o t h c e l l l i n e s i n r e s p e c t t o d o x o r u b i c i n . These compounds a r e s i g n i f i c a n t l y more l i p o p h i l i c t h a n those b e a r i n g hydroxy group a t t h e 3 ' - p o s i t i o n ( r e s u l t s n o t shown) . Table I .

C y t o t o x i c A c t i v i t y of A n t h r a c y c l i n e s M o d i f i e d on the Sugar Moiety i n Comparison w i t h Doxorubicin IC (ng/ml)

Compound

LoVo/Dx

LoVo

a

b

a

5 0

R.I.

doxorubicin

60

2180

36.3

7

40

875

21.8

10

18

495

27.5

11

100

263

2.6

12

5

45

9.0

18

11

10

0.9

IC

5 0

=

R.I.=

b

C o n c e n t r a t i o n i n h i b i t i n g c o l o n y g r o w t h by 5 0 % :4 treatment. r e s i s t e n c e i n d e x = (IC LoVo/Dx) / ( I C L o V o ) . 50

50

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147

Compound 18 was s e l e c t e d f o r i n v i v o t e s t s ( T a b l e I I ) . Notwithstanding i t s l a c k of c r o s s - r e s i s t a n c e , as evidenced i n v i t r o on LoVo/Dx c e l l s a n d i n s e v e r a l MDR c e l l s ( d a t a n o t shown) , t h e compound was f o u n d t o b e i n a c t i v e o n d i s s e m i n a t e d P388/DX l e u k e m i a . Table I I .

A c t i v i t y of 4 -Epi-amino Analog of Daunorubicin 18 Against P388 and P388/Dx Murine Leukemias 1

Tumor

a

O.D.

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(mg/kg)

a

T/C (%)

P388 i v

4.0

225

P388/Dx i v

5.2

121

O.D.= o p t i m a l

dose.

These r e s u l t s suggested t h a t among " c l a s s i c a l anthrac y c l i n e s " a l o w R.I. i n v i t r o i s n o t always a s s o c i a t e d w i t h m a i n t a i n a n c e o f i n v i v o a c t i v i t y on MDR t u m o r s . Morpholino S u b s t i t u t e d

Anthracyclines

Reductive a l k y l a t i o n of doxorubicin with 2,2'-oxybisa c e t a l d e h y d e i n the presence o f sodium c y a n o b o r o h y d r i d e l e d t o t h e d i s c o v e r y o f two o f t h e most p o t e n t a n t h r a c y c l i n e d e r i v a t i v e s : 3 ' -deamino-3 - (4-morpholino) d o x o r u b i c i n (19) a n d 3'-deamino-3'-(3-cyano-4-morpholino)doxorubicin (20), b o t h a c t i v e on s e n s i t i v e a n d MDR c e l l l i n e s (18,19). 1

Dx

19 : X=H k

J

20 : X = CN

XT I t c a n be h y p o t h e s i z e d t h a t the h i g h p o t e n c y o f m o r p h o l i n y l a n t h r a c y c l i n e s i s due t o a c o v a l e n t interaction of the m e t a b o l i c a l l y a c t i v a t e d m o r p h o l i n y l m o i e t y w i t h DNA (20,21) . However, t h e e x a c t mechanism o f a c t i o n i s s t i l l u n c l e a r . A s y n t h e t i c p r o g r a m was l a u n c h e d i n o u r l a b o r a t o r i e s t o p u r s u e o p t i m i z a t i o n o f t h i s c l a s s o f molecules and a better understanding of t h e i r s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s .

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When t h e 4 - m o r p h o l i n o r i n g was s h i f t e d f r o m t h e C-3' t o t h e C-4' p o s i t i o n ( e i t h e r e q u a t o r i a l o r a x i a l p o s i t i o n ) , t h e r e s u l t a n t m o r p h o l i n o d e r i v a t i v e s 21, 22, 23 w e r e f o u n d t o be e q u a l l y e f f e c t i v e o n b o t h c e l l l i n e s b u t t o h a v e no a c t i v i t y i n v i v o on d i s s e m i n a t e d P388 l e u k e m i a s . I t i s o f n o t e t h a t t h e o p t i m a l dose i s s i g n i f i c a n t l y h i g h e r t h a n t h a t of 3 '-morpholino d e r i v a t i v e s (Table I I I ) . Taken t o g e t h e r t h i s f i n d i n g s s u g g e s t a k e y r o l e f o r t h e C-3' p o s i t i o n i n t h e b i o l o g i c a l a c t i v i t y o f m o r p h o l i n o d e r i v a t i v e s o n MDR t u m o r s .

Table i l l .

C y t o t o x i c i t y on LoVo and LoVo/Dx C e l l s and Antitumor A c t i v i t y against P388 and P388/Dx Leukemias of 4 (morpholino)derivatives in comparison with 19 1

IC (ng/ml)

3.

P388

50

Compound

a

LoVo

19

171

21

21

22

852

23

203

LoVo/Dx

R.I.

1252

b

0.05

169

8.0

26

1381

1.6

-

3.1

c

T/C O.D. T/C O.D. (mg/kg) (%) (mg/kg) (%)

7.3

636

P388/DX

c

d

161

0.05

207

235

20

100

11.7

16.9

d

180

26

d

50

c d

111

I C = c o n c e n t r a t i o n i n h i b i t i n g c o l o n y growth by 50%: 4 h treatment. R . I . = r e s i s t e n c e i n d e x = (IC LoVo/Dx) / ( I C L o V o ) . O . D . = o p t i m a l dose h i g h e s t t e s t e d dose 5 0

b

106

50

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9. SUARATO ET AL.

Relationships of New Classes of Anthracyclines

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3 -(2-Alkoxy-4-morpholino)doxorubicin

149

Derivatives

An i m p o r t a n t c l a s s o f a n t h r a c y c l i n e s i s r e p r e s e n t e d b y t h o s e i n w h i c h a l k o x y r e s i d u e s a r e l i n k e d a t p o s i t i o n C-2 o f t h e 4-morpholino ring of doxorubicin. I n such compounds g l y c o s i d i c linkages a r e introduced i n t o t h e morpholino system, thus i n s e r t i n g a d d i t i o n a l chemical f e a t u r e t o t h e a n t h r a c y c l i n e . A number o f s u c h d e r i v a t i v e s h a v e b e e n s y n t h e s i z e d and t h e i r b i o l o g i c a l a c t i v i t y e v a l u a t e d . 3'-(2-Alkoxy-4-morpholino)anthracyclines of general f o r m u l a 24 h a v e b e e n p r e p a r e d b y c o n d e n s i n g 1 , 5 - d i i o d o - 2 a l k o x y - 3 - o x a p e n t a n e 25 w i t h d o x o r u b i c i n i n t h e p r e s e n c e o f t r i e t h y l a m i n e . D i i o d o d e r i v a t i v e s 25 a r e p r e p a r e d f r o m r i n g opening o f 1-alkyl-p-L-arajbino-pyranosides 26 a n d s u b s e q u e n t c h e m i c a l m o d i f i c a t i o n s (22) .

24

25

26

This procedure allows retention of c h i r a l i t y a t p o s i t i o n C - l f r o m t h e s t a r t i n g g l y c o s i d e t o p o s i t i o n C-2 o f t h e d i i o d o derivatives and gives 3'-(2-alkoxy-4-morpholino) a n t h r a c y c l i n e s w i t h d e f i n e d c h i r a l i t y a t C-2 (23). I n a d d i t i o n , b i s - a l k y l a t i o n o f t h e amino g r o u p o f a n t h r a c y c l i n e s a l s o a v o i d s t h e r e d u c t i o n o f t h e 1 3 - c a r b o n y l group, as r e p o r t e d by Acton d u r i n g t h e Borch r e d u c t i v e a l k y l a t i o n f o r t h e f o r m a t i o n o f t h e m o r p h o l i n o r i n g via b i s - a l d e h y d e (18) . The s t r u c t u r e s o f 2 - a l k o x y - 4 - m o r p h o l i n o a n t h r a c y c l i n e s a n d the c y t o t o x i c activity on LoVo a n d LoVo/DX c e l l s i n comparison w i t h 3 - (4-morpholino) d o x o r u b i c i n a r e r e p o r t e d i n Table IV. Among t h e 3 ' - ( 2 - a l k o x y - 4 - m o r p h o l i n o ) a n t h r a c y c l i n e s , t h e most active analogue was 3'-(2-methoxy-4-morpholino) d o x o r u b i c i n 24a; u n d e r t h e t e s t c o n d i t i o n s e m p l o y e d , t h i s compound showed a n R . I . v a l u e o f 3.5 a n d 6 f o l d i n c r e a s e i n p o t e n c y v e r s u s 3 ' - ( 4 - m o r p h o l i n o ) d o x o r u b i c i n . The d e c r e a s e d i n v i t r o a c t i v i t y r a n g i n g from 10-to 2 0 - f o l d , f o r analogues 24b-24e i n c o m p a r i s o n w i t h 24a was c o n s i s t e n t w i t h t h e i n c r e a s e d s t e r i c h i n d r a n c e a t C-2 o f t h e m o r p h o l i n o r i n g . On t h e o t h e r hand, t h e s e compounds were a c t i v e i n v i v o w i t h 1.5t o 1 0 - f o l d r e d u c e d p o t e n c y v e r s u s 24a. The a n t i t u m o r a c t i v i t y m e a s u r e d i n v i v o ( T a b l e V) c o n f i r m e d t h e l a c k o f c r o s s r e s i s t a n c e observed i n v i t r o . 1

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Table

ANTHRACYCLINE ANTIBIOTICS

IV.

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Compound

C y t o t o x i c A c t i v i t y o f (2-Alkoxy-4-morpholino) d o x o r u b i c i n D e r i v a t i v e s against LoVo and LoVo/Dx cells IC (ng/ml)

R LoVo

a

a

5 0

24a

CH

24b

C H

24c

CH(CH )

24d

CH C H

24e

C(CH )

32

3.5

104

356

3.4

106

517

4.9

154

530

3.4

243

830

3.4

9

3

2

5

3

2

6

2

5

3

3

R.I.

LoVo/Dx

b

I C = c o n c e n t r a t i o n i n h i b i t i n g c o l o n y g r o w t h b y 50%: 4 h treatment. R.I.= r e s i s t e n c e i n d e x = (IC LoVo/Dx) / (IC LoVo) . 5 0

b

50

Table V.

50

Antitumor A c t i v i t y o f (2-Alkoxy-4-morpholino) d o x o r u b i c i n D e r i v a t i v e s against P388 and P388/Dx Leukemias P388/DX

P388 Compound

R

24a

CH

24b

C H

24c

CH(CH )

24d

CH C H

24e

3

2

5

3

2

6

5

C(CH ) 3

2

3

a

O.D.

T/C

O.D.

T/C

(mg/kg)

(%)

(mg/kg)

(%)

0.09

250

0.11

208

0.22

219

0.16

189

0.50

200

0.50

167

0.50

175

0.50

156

200

1.00

172

a

0.45

a

O.D.= o p t i m a l d o s e .

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9. SUARATO ET AL.

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Relationships of New Classes of Anthracyclines 1

On the b a s i s of the above r e s u l t s , the e f f e c t of 3 - (2methoxy-4-morpholino)doxorubicin was explored on d i f f e r e n t leukemias and s o l i d tumors i n mice, and the r e s u l t s of biological a c t i v i t y assays, i n comparison w i t h those of d o x o r u b i c i n , are i l l u s t r a t e d i n Table VI and V I I . This compound showed c l e a r a c t i v i t y on MDR c e l l s and tumors and was also found more effective than doxorubicin i n experimental s o l i d neoplasms, such as the MX1 and mammary carcinomas. The compound i s now undergoing Phase I c l i n i c a l trials (24). 1

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Table V I .

Comparative Activity of 3 -(2-Methoxy-4morpholino) d o x o r u b i c i n 24a and D o x o r u b i c i n

Experimental model

3

P388

+++

P388/Dx Johnson

+++

P388/DX

Schabel

L1210

a b

Compound 24a

++

Doxorubicin

15

+++

---

++

++

L1210/CDDP

+

+

L1210/L-PAM

+

+

Disseminated leukemias; compounds were a d m i n i s t e r e d i v . T/C%: +, 130-150; ++, 150-200; +++, >200.

Table V I I .

Comparative 3* -(2-Methoxy-4Activity of morpholino 80.

Priebe; Anthracycline Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

3

152 3

1

ANTHRACYCLINE ANTIBIOTICS

-(2-Acyloxy-4-morpholino)doxorubicin

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I n o r d e r t o e x p l o r e t h e i n f l u e n c e on MDR tumor c e l l s o f other classes of modified at 4-morpholino ring a n t h r a c y c l i n e s , we d e c i d e d t o s u b s t i t u t e o n t h a t m o i e t y a t p o s i t i o n C-2 g r o u p s w i t h d i f f e r e n t p o l a r i t y t h a n t h e a l k o x y . C o n s e q u e n t l y , we c h o s e t o s y n t h e s i z e 3 ' - ( 2 - a c y l o x y 4 - m o r p h o l i n o ) a n t h r a c y c l i n e s . The l e a d i n g compound o f t h i s c l a s s o f a n t h r a c y c l i n e s i s 3'-(2-0-benzoyl-4-morpholino)d o x o r u b i c i n 27, w h i c h was p r e p a r e d v i a B o r c h r e d u c t i v e a l k y l a t i o n o f d o x o r u b i c i n w i t h b i s - a l d e h y d e 28 o b t a i n e d f r o m p e r i o d a t e o x i d a t i o n o f 29 ( 2 5 ) . ODx

28

29

3 ' - ( 2 - 0 - b e n z o y l - 4 - m o r p h o l i n o ) d o x o r u b i c i n was endowed w i t h a n R . I . v a l u e o f 3.9 a n d i n v i v o a n t i t u m o r a c t i v i t y comparable to that of 3'-(2-alkoxy-4-morpholino) d e r i v a t i v e s , w i t h %T/C o f 200 a n d 167 a t a n o p t i m a l d o s e o f 0.5 mg/kg o n b o t h d i s s e m i n a t e d P388 a n d P388/DX l e u k e m i a s . T h e s e . r e s u l t s a r e s i m i l a r t o t h o s e o b t a i n e d i n t e s t i n g 3'( 2 - O - b e n z y l - 4 - m o r p h o l i n o ) d o x o r u b i c i n 24d, i n d i c a t i n g t h a t s t e r i c f a c t o r s , r a t h e r t h a n e l e c t r o n i c e f f e c t s , a r e more important i n i n f l u e n c i n g t h e potency and a c t i v i t y o f a n t h r a c y c l i n e s s u b s t i t u t e d a t p o s i t i o n C-2 i n t h e 3 ' - ( 4 mo r p h o 1 i ηο) s y s t em.

Mustard A n t h r a c y c l i n e s R e c e n t l y , a new d i s t i n c t c l a s s o f a n t h r a c y c l i n e s a c t i v e o n MDR tumor c e l l s was d e v e l o p e d i n our laboratories. Structure-relationships data collected from different c l a s s e s o f a n t h r a c y c l i n e s p r o m p t e d u s t o d e s i g n new molecules capable o f both i n t e r c a l a t i n g and a l k y l a t i n g a t DNA. B a s e d on t h e d a t a c o l l e c t e d , i t was w o r t h w h i l e t o i n t r o d u c e a n a l k y l a t i n g m o i e t y a t p o s i t i o n C-3' o f t h e aminosugar, this i d e a was a l s o s u p p o r t e d by recent

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9. SUARATO ET AL.

153

Relationships of New Classes of Anthracyclines

s p e c t r o s c o p i c evidence i n d i c a t i n g the o r i e n t a t i o n of the 3 '-methoxymorpholinyl moiety w i t h i n the minor groove of DNA h e l i x , near the ATbase p a i r s (26). We chose the c l a s s i c a l n i t r o g e n mustard i n which the n i t r o g e n atom was that of the 3 -amino group of a n t h r a c y c l i n e g l y c o s i d e . In a d d i t i o n , a hindered withdrawing group, such as a m e t h y l s u l f o n i c group, was attached at p o s i t i o n C-4' with the aim of reducing the b a s i c i t y of the n i t r o g e n mustard. The l e a d i n g compound of t h i s new c l a s s of molecules i s 4-demethoxy-3 ' - b i s (2-chloroe t h y l ) - 4 *-deoxy-4'-O-sulfonyl-daunorubicin 3 0 , prepared by r e a c t i n g 4-demethoxydaunorubicin 3 1 with ethylene oxide t o g i v e the 3'-N-bis(2-hydroxyethyl) d e r i v a t i v e 3 2 , which i s converted i n one step to 3 0 by treatment with mesyl c h l o r i d e i n p y r i d i n e (27) .

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1

30

31

32

The compound showed an R.I. value of 3.5. P r e l i m i n a r y b i o l o g i c a l data, reported i n Table V I I I , i n d i c a t e that t h i s new type of s u b s t i t u t i o n may represent a breakthrough i n the f i e l d of new a n t h r a c y c l i n e s . Table V I I I .

Antitumor A c t i v i t y of Compound 30 a g a i n s t P3 8 8 and P3 88/DX Leukemias P388/DX

P388 Compound

30

a

LTS:

Dose

T/C

(mg/kg)

(%)

4.8

481

long term s u r v i v a l s experiments.

LTS

a

3/10

T/C

Dose

a

(mg/kg)

(%)

4.8

233

2/19

6.2

>410

9/19

(>60 days)

after

end of

Literature cited 1. 2.

LTS

Gottesman,M.M. Cancer Res. 1993, 53, 747-754. Kaye,S.B. Br.J.Cancer 1988, 58, 691-694.

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the

154 3. 4. 5. 6. 7. 8.

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9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

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vanKalten,C.K; Pinedo,H.M; Giaccone, G. Eur.J.Cancer 1991, 27, 1481-1486. Beck,W.T. Eur.J.Cancer 1 9 9 0 , 26, 513-515. Dalton,W.S; Grogan,T.M; Meltzer,P.S. J.Clin.Oncol. 1 9 8 9 , 7, 415-424. Drewinko,B; Romsdahl,M.M; Yang,M.Y; Ahearn,M.J; T r u j i l l o , J . M . Cancer Res. 1 9 9 0 , 36, 467-475. Grandi,M; Geroni,C; G i u l i a n i , F . C . Br.J.Cancer 1 9 8 6 , 54, 515-518. Geran,R.I; Greenberg,N.H; MacDonald,M.M; Shumaker, A.M; Abbot,B.J. Cancer Chem.Rep. 1972, Part 3, 1-103. Johnson,R.K; Chitnis,M.P; Embery,W.M; Gregory,E.B. Cancer Treat.Rep. 1978, 62, 1535-1547. Arcamone,F. Doxorubicin, Medicinal Chemistry; Academic Press: New York, N . Y . , 1981, Vol.17. Facchetti,I; Grandi,M; Cucchi,P; Geroni,C; Penco,S; Vigevani,A. Anti-Cancer Drug Design 1991, 5, 385-397. Suarato,A; Angelucci,F; Bargiotti,A. Chimicaoggi 1 9 9 0 , 8, 9. Bargiotti,A; Caruso,M; Suarato,A; Penco,S; G i u l i a n i , F . U.S.Patent 1987, 4,684,629. Suarato,A; Caruso,M; Penco,S; G i u l i a n i , F . GB Patent 1 9 8 8 , 2195998A. Bargiotti,A; Suarato,A; Z i n i , P ; Grandi,M; Pezzoni,G. U.S.Patent 1991, 4,987,126. Suarato,A; Bordoni,T; Caruso,M; Barbieri,B; Bargiotti, A; Geroni,C; Arcamone,F; G i u l i a n i , F . Proc. Amon.Assoc. Cancer Res. 1987,2721. G i u l i a n i , F ; Fiebig,H.H; Pezzoni,G; Bahari,B; Caruso,M; Bargiotti,A; Suarato,A. NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, 1989. Acton,E.M; Tong,G.L; Mosher,C.W; Wolgemuth,R.L. J.Med.Chem. 1984, 27, 638-645. Johnston,J.B; Habernicht,B; Acton,E.M. Biochem. Pharmacol. 1983, 32, 3255-3258. Westendorf,J; Groth,G; Steinheider,G; Marquardt,H. J.Cell Biol.Toxicol. 1 9 8 5 , 1, 87-101. Westendorf,J; Aydin,M; Groth,G; Weller,O; Marquardt,H. Cancer Res. 1989, 49, 5262-5266. Suarato,A; Angelucci,F; Bargiotti,A; Grandi,M;Pezzoni, G. G.B. Patent 1989, 8905668 Faiardi,D; Bargiotti,A; Grandi,M; Suarato,A. G.Β.Patent 1 9 8 9 , 8928654. Bargiotti,A; Faiardi,D; Grandi,D; Ripamonti,M;Suarato, A. XVIth International Carbohydrate Symposium 1992, Paris, A164. Ripamonti,M; Pezzoni,G; Pesenti,E; Pastori,A; Farao,M; Bargiotti,A; Suarato,A; Spreafico,F; Grandi,M. Br.J. Cancer 1 9 9 2 , 65, 703-707. Faiardi,D; Bargiotti,A; Suarato,A. G.B. Patent 1991, 9019934.

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27. 28.

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155

Odefey,C; Westendorf,J; Johannes,D; Dieckmann,Τ; Oshkinat,T. Chem.-Biol.Interact. 1 9 9 2 , 85(2-3), 117122. Bargiotti,A; Caruso,M; Faiardi,D; Suarato,A; Mongelli, N. G.B. Patent 1991, 9114549

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RECEIVED June 3, 1994

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