Synthesis and cytotoxicity of phenyl-vinyl derivatives of 4,6,6-trimethyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile

Abstract

2-bromophenyl derivatives showed high cytotoxic activity towards both cell lines. The toxicity towards NIH 3T3 normal mouse embryonic fibroblasts depends on the nature and position of the substituent in the phenyl ring. The greatest selectivity of cytotoxic effect was seen in the 2-bromophenyl derivative.In the synthesis of novel antitumor compounds the method of introducing a δ-lactam [1][2][3][4] or cyanovinyl group [5-9] into the starting molecule has been successfully used. A δ-lactam ring is included in camptothecin series antitumor preparations (inhibitors of topoisomerase I [10] -irinotecan [10, 11], rubitecan [12], topotecan [10, 13], exatecan [14], and its metabolite 9-aminocamptothecin [15], silatecan [16], and also inhibitors of dihydrofolate reductase (pemetrexed [17]), thymidyl synthetase (raltitrexed [18]), and farnesyl transferase (tipifarnib [19]). A δ-lactam ring occurs in the structure of an immunoregulator [20] and the antiangiogenic agent roquinimex [21]. N H Me Me O Me N N H Me O Me N H O R 1 2-26 R EtOH, NaOH , 25-78°C

Crystal structure of 4-[2-(2-chlorophenyl)vinyl]-6,6-dimethyl- 2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile, C16H15ClN2O

“…Results of biological studies show that the title compound indicates avery high cytotoxicity in vitro in relation of multilayer tumor cells of HT-1080 (humanf ibrosarcoma) and MG 22A (mousehepatoma) (LD 50 2-3 mg/ml) [1]. The synthesized title compound has been identified on the basis of 1 H-NMRspectra andelemental analysis data.According to 1 HNMRspectroscopyinCDCl 3 solution theexocycledoublebond hasatrans conformation (J =1 6.3 Hz) [ 1].…”

“…The synthesized title compound has been identified on the basis of 1 H-NMRspectra andelemental analysis data.According to 1 HNMRspectroscopyinCDCl 3 solution theexocycledoublebond hasatrans conformation (J =1 6.3 Hz) [ 1]. X-Ray diffraction analysis of single crystals of this substance was performed in order to obtain objective detailed information about the spatial and geometric structure of the title compound.…”

“…Thesynthesis of thetitlecompoundwas performed by condensation of 4,6,6-trimethyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonyl with 2-chlorobenzaldehyde in ethanol solution in presence of catalyticamount of NaOH [1]. Single crystals of the compound were obtained by slow crystallization from ethanol solution at room temperature.…”

Tetrahydropyridine: a promising heterocycle for pharmacologically active molecules

“…Disubstituted compounds showed more activity than monosubstituted but were also found to be more toxic. 59 more potent for 5-HT 7 than other 5-HT receptors subtypes. The distance between tetrahydrobenzindole and tetrahydrothienopyridine is important and four carbon chain lengths were found to be optimum for selectivity to 5-HT 7 receptors.…”

Catalyzed reaction of enaminonitrile with primary amines by SbF3: synthesis of new 2-aminosubstituted-pyridine-fused δ-lactones

“…In this paper we focus on extending our preliminary results concerning butenolide aminopyridines to new 2aminopyridines fused with a six-membered lactone (Figure 1). It should point out that the δ-lactone nitrile 1 used, was previously studied by Lukevics et al 20,21…”