1 Development of
(N)-Heterocyclic Carboxaldehyde
Thiosemicarbazones with Clinical Potential as Antineoplastic Agents ALAN C. SARTORELLI and KRISHNA C. AGRAWAL
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Department of Pharmacology and Section of Developmental Therapeutics, Division of Oncology, Yale University School of Medicine, New Haven, Conn. 06510 The initial r e p o r t of the- a n t i n e o p l a s t i c activity o f an ( N ) - h e t e r o c y c l i c carboxaldehyde thiosemicarbazone was made i n 1956 by Brockman and h i s a s s o c i a t e s (1) who reported that 2-formylpyridine thiosemicarbazone (PT) produced an increase i n the life span of mice bearing the L1210 leukemia; the f u r t h e r devel opment o f t h i s compound as a p o t e n t i a l cancer chemotherapeutic agent was c u r t a i l e d , however, because o f its relatively low ther apeutic index. Several years l a t e r , French and Blanz (2,3) des c r i b e d the synthesis o f 1-formylisoquinoline thiosemicarbazone (IQ-1) and a v a r i e t y o f other ( N - h e t e r o c y c l i c carboxaldehyde thiosemicarbazones. These i n v e s t i g a t i o n s demonstrated that s e v e r a l h e t e r o c y c l i c r i n g systems, i n c l u d i n g p y r i d i n e , isoquinol i n e , q u i n a z o l i n e , phthalazine, pyrazine, p y r i d a z i n e , and purine possessed s i g n i f i c a n t a n t i n e o p l a s t i c activity when the carbonyl attachment o f the s i d e chain was l o c a t e d at a p o s i t i o n to the to the r i n g n i t r o g e n atom; attachment of the side chain βor h e t e r o c y c l i c Ν atom r e s u l t e d i n i n a c t i v e antitumor agents. Members of t h i s c l a s s have shown a n t i c a n c e r activity against a wide spectrum o f t r a n s p l a n t e d rodent neoplasms, i n c l u d i n g Sar coma 180, E h r l i c h carcinoma, Leukemia L1210, Lewis lung c a r c i noma, Hepatoma 129, Hepatoma 134, Adenocarcinoma 755, and B16 melanoma. In a d d i t i o n , spontaneous lymphomas o f dogs have shown ( N ) - h e t e r o c y c l i c carboxaldehyde thiosemicar s u s c e p t i b i l i t y to bazones. Such broad spectrum activity denotes great clinical p o t e n t i a l and suggests that a drug o f t h i s c l a s s may w e l l have utility i n cancer therapy. Extensive m o d i f i c a t i o n o f the formyl thiosemicarbazone side chain o f IQ-1 was c a r r i e d out by Agrawal and Sartorelli (4) to a s c e r t a i n the importance o f t h i s p a r t of the molecule f o r a n t i cancer a c t i v i t y . A v a r i e t y o f the s u b s t i t u t i o n s and a l t e r a t i o n s of the various p o s i t i o n s o f the side chain that were made are shown i n Figure 1; these changes uniformly l e d to complete l o s s or marked decrease i n t u m o r - i n h i b i t o r y potency. In a d d i t i o n , replacement of the h e t e r o c y c l i c r i n g Ν with C a l s o r e s u l t e d in a biologically i n a c t i v e compound. These f i n d i n g s i n d i c a t e d the
1
In Cancer Chemotherapy; Sartorelli, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 1976.
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2
CANCER
Figure 1.
Some modifications of the side chain of thiosemicarbazone
CHEMOTHERAPY
1-formylisoquinoline
In Cancer Chemotherapy; Sartorelli, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 1976.
Downloaded by SEATTLE UNIV on July 9, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0030.ch001
1.
SARTORELLI AND AGRAWAL
Antineoplastic
Agents
3
e s s e n t i a l i t y o f t h i s p o r t i o n o f the molecule and supported the i n i t i a l suggestion o f French and Blanz (3) that a conjugate N*-N*-S* t r i d e n t a t e l i g a n d system was a r e q u i s i t e f o r tumor i n hibitory activity. Extensive s u b s t i t u t i o n o f the i s o q u i n o l i n e and p y r i d i n e r i n g systems o f ( N ) - h e t e r o c y c l i c carboxaldehyde thiosemicarbazones has been c a r r i e d out by our l a b o r a t o r y (5-10) and by Blanz et a l . (11,12). A d e t a i l e d summary o f the e f f e c t s o f some o f these subs t i t u e n t s on a n t i n e o p l a s t i c e f f i c a c y has been reported (13,14). Unfortunately, these i n v e s t i g a t i o n s have not allowed d e t a i l e d p r e d i c t i o n s to be made concerning the importance o f these m o d i f i c a t i o n s to the a c t i v i t y o f t h i s c l a s s o f agents against neoplas tic cells. The
