Poster Presenter

Synthesis Of 1,3,4-Oxadiazol-2-Y1 Tetrahydropyridines As Anti-Cancer Agents
Kinfe Ken Redda, Kinfe Ken Redda and Madhavi Gangapuram
USA

Tetrahydropyridine (THP) ring moieties have attracted synthetic interests for being essential structures in many medicinal agents. In addition, 1,3,4-oxadiazoles and their derivatives were reported to possess potential antimicrobial, antifungal, anti-inflammatory and anti-cancer agents. The anti-inflammatory and anti-cancer activities of compounds consisting of reduced pyridine ring systems were investigated in our laboratory. Our earlier research indicated that the pharmacological activities of the THP derivatives depended on the nature of the substituents on THP ring system. It was postulated that incorporation of the THP moiety might enhance the biological activity of 1,3,4-oxadiazole derivatives. Thus, the design and synthesis of novel series of 1,3,4-oxadiazoles containing carbonyl/sulfonyl tetrahydropyridine moieties with potential as anti-cancer and anti-inflammatory activities were initiated. In the current investigation, we synthesized many analogs maintaining the 1,3,4-oxadiazol-2-yl benzoyl/benzenesulfonyl amino-1,2,3-6-tetrahydropyridine analog having modifications on both the oxadiazole and phenyl rings. We incorporated substituents on the rings that could affect the molecule’s electron density, lipophilicity and steric configurations.

The starting material was 4-(5-methyl/phenyl-1,3,4-oxadiazol-2yl)pyridine obtained by the reaction of isonicotinic acid hydrazide and triethyl orthoacetate/orthobenzoate which were heated under reflux for 24 h. O-mesitylene sulfonyl hydroxyl amine (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 benzoyl chlorides/benzenesulfonyl chlorides in anhydrous tetrahydrofuran containing triethylamine gave stable benzoyl/benzenesulfonyl imino ylides. This was followed by reduction with sodium borohydride in absolute ethanol, which furnished the target compounds 1-(substituted benzoyl/benzenesulfonylamino)-4-(5-methyl/phenyl-1,3,4-oxadiazol-2-yl)-1,2,3,6-tetrahydro-pyridine. These compounds were evaluated for their anti-inflammatory activity using the cyclooxyginase-1 (COX-1) and COX-2 inhibition assays (indomethacin as a reference control) and in vitro activity on MCF-7 breast cancer cell lines. The cytotoxicity activities of the compounds were tested using tomaxifen as a control. All the compounds tested showed inhibition of COX-1 and COX-2, almost nonselectively. The 4-methylbenzenesulfonyl amino THP analog containing the 5-phenyl-1,3,4-oxadiazol-2-yl substituent showed the highest COX-2 preference (COX-1/COX-2 = 2.11). This compound also exhibited the most potent cytotoxicity with an IC50 value of 22.02 μg/mL.

This research was supported by NIH/RCMI Grant # G12 RR03020 and Pharmaceutical Research Center NIH/NCRR Grant 1 C06 RR12512-01.