K. Redda, Madhavi Gangapuram
May 1, 2007
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Journal
Cancer Research
Abstract
3981 The chemistry of substituted 1,3,4-oxadiazoles and their derivatives received considerable attention during the last decade as potential antimicrobial, antifungal, anti-inflammatory, analgesic, CNS-stimulating, anticonvulsive, anti-cancer, diuretic and antihypertensive agents. Functionalized tetrahydropyridine (THP) ring systems are widely found in biologically active natural products and pharmaceuticals. The anti-inflammatory and anticancer activities of compounds consisting of a reduced pyridine system have been investigated. From our previous research, it was evident that the pharmacological activities of the tetrahydropyridine (THP) derivatives depended on the nature of the substituents on the THP ring system. Incorporation of potential THP moiety may enhance biological activity of 1,3,4-oxadiazole derivatives. Hence, it was planned to synthesize 1,3,4-oxadiazolyl tetrahydropyridines and study their anti-cancer activities. Here, we report the synthesis and anti-cancer activity profiles of a novel series of 1,3,4-oxadiazoles containing carbonyl/sulfonyl tetrahydrohydropyridine moiety. In the current investigation, we have synthesized many analogs maintaining the 1,3,4-oxadiazole-1,2,3,6-tetrahydropyridine ring and having modifications on the oxadiazole, phenyl ring. in order to compare their biological activities. The starting compound was 4-(5-methyl/phenyl-1,3,4-oxadiazol-2-yl)pyridine obtained by the reaction of isonicotinic acid hydrazide and triethyl orthoacetate/orthobenzoate which were heated under reflux for 24 h. O-mesitylene sulfonyl hydroxylamine (MSH) was used to prepare the N-amino salt as an aminating agent. Mesitylene sulfonyl chloride was added with stirring to a solution of ethylacetohydroxymate and triethylamine in dimethylformamide at 0o C. Hydrolysis of this compound with the mixture of p-dioxane- 70% perchloric acid and allowing them to react for 45 min, gave a white solid of MSH. 4-(5-Methyl/phenyl-1,3,4-oxadiazol-2-yl)pyridine was reacted with MSH in dichloromethane to produce 1-amino-4-(5-methyl/phenyl-1,3,4-oxadiazol-2-yl)pyridine mesitylenesulfonate. Reaction of the amino salt with substituted acid chlorides/sulfonyl chlorides in anhydrous tetrahydrofuran containing triethylamine gave stable ylides. This was followed by reduction with Sodium borohydride in absolute ethanol, which furnished the target compounds 1-(substituted phenylcarbonyl/sulfonylamino)-4-(5-methyl/phenyl-1,3,4-oxadiazole)-1,2,3,6-tetrahydropyridine. The biological activities of these compounds were evaluated in vitro on MCF-7 breast cancer cell lines. The novel compounds displayed moderate cytotoxicity. This research was supported by NIH/RCMI Grant (RCMI) # G12 RR03020 and Pharmaceutical Research Center NIH/NCRR grant 1 C06 RR12512-01.