Synthesis and Biological Activities of Conformationally Restricted, Tricyclic Nonclassical Antifolates as Inhibitors of Dihydrofolate Reductases

Abstract

Seven novel tricyclic pyrimido[4,5-c][2,7]naphthyridones 5-8 and the corresponding naphthyridines 9-11 were synthesized as conformationally restricted inhibitors of dihydrofolate reductase (DHFR) and as antitumor and/or antiinfectious agents. The analogues were designed to orient the side chain trimethoxyphenyl group in different conformationally defined positions in order to explore the effect of the side chain orientation on binding affinity and selectivity for DHFR from various species. The semirigid orientations were achieved by bridging the C5 and N10 of compound 12 with a N-ethyl bridge and by variation of the position of double bonds in rings B and C as well as substitution at the 2',6'-positions of the phenyl ring. The synthesis of compounds 5-11 were accomplished by cyclocondensation of the appropriate keto ester (as the biselectrophile) with 2,4,6-triaminopyrimidine to afford the lactam 5. The dehydrolactams 6 and 7 were prepared by air oxidation and PtO2-catalyzed dehydrogenation of 7, respectively. The dichloro dehydro lactam 8 was obtained by refluxing lactam 5 and/or 6 in POCl3 or a mixture of POCl3/PCl5. Compounds 9-11 were obtained by two methods, direct borane reduction of lactam 5 or 6 or thiation of the dipivoylated lactam 15 followed by reductive dethiation. Compounds 9-11 were interconverted by air oxidation or PtO2-catalyzed reduction/oxidation, respectively. The compounds were evaluated as inhibitors of DHFR from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) with rat liver (rl) serving as the reference mammalian enzyme. In the lactam series 5-8, the most unsaturated analogue 7 showed an IC50 of 86 nM against rlDHFR, almost 100-fold more active than 5 and 3-fold more active than 6. The 2',6'-dichloro dehydro lactam 8 was less active than the corresponding dehydro lactam 6 against rlDHFR. In the naphthyridine series 9-11, the dehydro analogue 10 was more active than 9 against rlDHFR. The fully reduced analogue 11 (as a mixture of cis and trans isomers) was the most active in the naphthyridine series. The analogues were, in general, more inhibitory against rlDHFR than against pcDHFR, or tgDHFR, and thus lacked selectivity. In addition, they were less potent than the bicyclic compounds trimetrexate 3 (TMQ) and piritrixim 4 (PTX).

Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3‐d]pyrimidine antifolates

“…Though compound 7 was the primary target, we were very much interested in the partially reduced analogues 4 and 6 as well as the essentially planar analogue 5. The varying levels of unsaturation in rings B and C of 4-7 provide subtle variations in the tricyclic ring conformation which provides increased potency and/or selectivity as we have previously reported for the pyrido annulated analogues [26]. In fact, in the tricyclic series 3, the most selective Gangjee et al [28] reported a novel strategy for the synthesis of the tricyclic pyrido [2,3-d]pyrimidines via a Fischer indole type cyclization of a 2-amino-4-oxo hydrazone.…”

“…Gangjee et al [26] recently reported the tricyclic pyrido annulated analogues in which the C5 and N10 were tethered via an ethyl link effectively restricting the 9-10 bridge. Some members of this series of conformationally restricted tricyclic analogues represented by general structure 3 were potent inhibitors of rat liver dihydrofolate reductase with inhibitory constants (IC 50 ) which were highly potent (IC 50 86 nM, for 3 R 1 = 3,4,5-OMePh, R 2 = OH) but the series lacked selectivity for P. carinii or T. gondii dihydrofolate reductase and were in fact much more inhibitory against mammalian dihydrofolate reductase.…”

Synthesis of New Trisubstituted 4‐Aminopiperidines as PAF‐Receptor Antagonists

“…As outlined in Scheme 1, compound 5 was obtained in good yield from 3,3Ј-[(phenylmethyl)imino]bis(propanenitrile) [57,58] after Thorpe intramolecular cyclization using sodium amide in refluxing THF. [59] As for the corresponding ester 3, several strategies to prepare N-acylated or Nalkylated compounds were investigated but all failed, probably for the reasons we evoked in the ester 3 case.…”

Design, synthesis, and antitumor screening of certain novel tetrahydroquinoline sulfonamides

“…In that context, several quinoline derivatives have been shown to exhibit high affinity for receptor tyrosine kinases (RTKs), as well as other oncogenic targets, and to possess remarkable antitumor activity both in vitro and in vivo [1][2][3][4][5][6][7] . Many new sulfonamide derivatives, such as HMN-214, E7010 (ABT-751), and E7070 (Indisulam), have shown substantial antitumor activity via different mechanisms as multidrug resistance down-regulation, tubulin polymerization, inhibition of receptor tyrosine kinases (RTKs) among others [8][9][10][11][12][13][14][15][16][17][18][19][20][21] . Recently, the mechanism of sulfonamide antitumor activity has been reported to involve inhibition of carbonic anhydrase (CA) isoforms IX and XII [19][20][21] .…”

“…Many new sulfonamide derivatives, such as HMN-214, E7010 (ABT-751), and E7070 (Indisulam), have shown substantial antitumor activity via different mechanisms as multidrug resistance down-regulation, tubulin polymerization, inhibition of receptor tyrosine kinases (RTKs) among others [8][9][10][11][12][13][14][15][16][17][18][19][20][21] . Recently, the mechanism of sulfonamide antitumor activity has been reported to involve inhibition of carbonic anhydrase (CA) isoforms IX and XII [19][20][21] . Therefore, in this work, we will prepare some acrylamide containing sulfonamide derivatives and will study their activity against some selected cell lines.…”