Comparison of the biological effects of selected 5,8-dideazafolate analogs with their 2-desamino counterparts

Abstract

Three new 5,8-dideaza analogues of folic acid devoid of an amino group at position 2 have been prepared by using synthetic routes patterned after earlier methodologies. They were 2-desamino-5,8-dideazaisofolic acid, 2b, 2-desamino-10-thia-5,8-dideazafolic acid, 2c, and 2-desamino-10-oxa-5,8-dideazafolic acid, 2d. These compounds were found to be 4-6-fold more cytoxic toward L1210 leukemia cells than their 2-NH2 counterparts and to be poor inhibitors of mammalian thymidylate synthase. However, they were only 1.5-3-fold less inhibitory toward dihydrofolate reductase than the analogous compounds containing a 2-NH2 group. The known thymidylate synthase inhibitors 2-desamino-10-propargyl-5,8-dideazafolic acid and 10-propargyl-5,8-dideazafolic acid were included in this study for purposes of comparison.

Thymidylate synthase inhibition: A structure-based rationale for drug design

“…[83][84][85][86][87][88][89][90][91][92][93][94][95][96] In particular, the quinoline derivatives are still active as TS inhibitors and can be regarded as classical antifolates in the low micromolar and nanomolar range 83 (Fig. 10).…”

Quinazoline antifolate thymidylate synthase inhibitors: bridge modifications and conformationally restricted analogs in the C2-methyl series

“…The overall strategy for the synthesis of the reversed bridge compounds [14][15][16][17][18][19][20][21][22][23][24][25][26] was the sequential alkylation of 6-amino-2-methylquinazolinone (33)" with the appropriate alkyl halides in NJV-dimethylformamide (DMF) using CaCOg to scavenge HBr (Scheme I). The reduction of the nitro compound 32 by hydrogen over 10% Pd-C gave 33 Compounds not numbered were prepared by the same methods as those shown in the appropriate schemes.…”

“…of the CH2N bridge have been synthesized by Hynes and his colleagues in the C2-amino series18"20 and more recently in the C2-desamino series. 21 The prototype in this class IAHQ (13)1W2 has the reversed N9,C10 bridge between the two aromatic rings rather than the normal C9,N10 configuration. IAHQ is a potent cytotoxic agent in a number of cell lines23,24 despite having only 1% of the potency of 1 as an inhibitor of TS.…”

“…IAHQ is a potent cytotoxic agent in a number of cell lines23,24 despite having only 1% of the potency of 1 as an inhibitor of TS. 21 As with 1 and its C2-methyl analogues, thymidine alone protects against this cytotoxicity and there is now considerable evidence23,24 that IAHQ is extensively metabolized intracellularly to poly-7glutamate derivatives that are the potent TS inhibitors responsible for the cytotoxic activity. The isosteric 10-oxa (27) and 10-thia (28) analogues were also highly cytotoxic to L1210 cells and effective substrates for mammalian folylpolyglutamate synthetase (FPGS).…”

“…The isosteric 10-oxa (27) and 10-thia (28) analogues were also highly cytotoxic to L1210 cells and effective substrates for mammalian folylpolyglutamate synthetase (FPGS). 21 In general the C2-desamino derivatives of these C9,N10 isosteres are 3-6-fold more cytotoxic than their C2-amino counterparts despite being less potent against TS itself.21 We were encouraged by these reports to incorporate isosteric replacements for the bridge region into some of our recent quinazoline antifolate structures where C2-methyl and benzoyl ring modifications have given extremely potent cytotoxic agents.…”