Click-chemistry mediated synthesis of OTBN-1,2,3-Triazole derivatives exhibiting STK33 inhibition with diverse anti-cancer activities

There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of 4′-((4-substituted-4,5-dihydro-1H-1,2,3-triazol-1-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile (OTBN-1,2,3-triazole) derivatives were synthesized by click chemistry. The series of bioactive compounds were designed and synthesized from diverse alkynes and N3-OTBN, using copper (II) acetate monohydrate in aqueous dimethylformamide at room temperature. Besides being highly cost-effective and significantly reducing synthesis, the reaction yielded 91–98 % of the target products without the need of any additional steps or chromatographic techniques. Two analogues exhibit promising anti-cancer biological activities. Analogue 4l shows highly specific cytostatic activity against lung cancer cells, while analogue 4k exhibits pan-cancer anti-growth activity. A kinase screen suggests compound 4k has single-digit micromolar activity against kinase STK33. High STK33 RNA expression correlates strongly with poorer patient outcomes in both adult and pediatric glioma. Compound 4k potently inhibits cell proliferation, invasion, and 3D neurosphere formation in primary patient-derived glioma cell lines. The observed anti-cancer activity is enhanced in combination with specific clinically relevant small molecule inhibitors. Herein we establish a novel biochemical kinase inhibitory function for click-chemistry-derived OTBN-1,2,3-triazole analogues and further report their anti-cancer activity in vitro for the first time

Click-chemistry mediated synthesis of OTBN-1,2,3-Triazole derivatives exhibiting STK33 inhibition with diverse anti-cancer activities

There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of 4′-((4-substituted-4,5-dihydro-1H-1,2,3-triazol-1-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile (OTBN-1,2,3-triazole) derivatives were synthesized by click chemistry. The series of bioactive compounds were designed and synthesized from diverse alkynes and N3-OTBN, using copper (II) acetate monohydrate in aqueous dimethylformamide at room temperature. Besides being highly cost-effective and significantly reducing synthesis, the reaction yielded 91–98 % of the target products without the need of any additional steps or chromatographic techniques. Two analogues exhibit promising anti-cancer biological activities. Analogue 4l shows highly specific cytostatic activity against lung cancer cells, while analogue 4k exhibits pan-cancer anti-growth activity. A kinase screen suggests compound 4k has single-digit micromolar activity against kinase STK33. High STK33 RNA expression correlates strongly with poorer patient outcomes in both adult and pediatric glioma. Compound 4k potently inhibits cell proliferation, invasion, and 3D neurosphere formation in primary patient-derived glioma cell lines. The observed anti-cancer activity is enhanced in combination with specific clinically relevant small molecule inhibitors. Herein we establish a novel biochemical kinase inhibitory function for click-chemistry-derived OTBN-1,2,3-triazole analogues and further report their anti-cancer activity in vitro for the first time

A green bio-organic catalyst (taurine) promoted one-pot synthesis of (R/S)-2-thioxo-3,4-dihydropyrimidine(TDHPM)-5-carboxanilides: chiral investigations using circular dichroism and validation by computational approaches

Owing to the massive importance of dihydropyrimidine (DHPMs) scaffolds in the pharmaceutical industry and other areas, we developed an effective and sustainable one-pot reaction protocol for the synthesis of (R/S)-2-thioxo-DHPM-5-carboxanilides via the Biginelli-type cyclo-condensation reaction of aryl aldehydes, thiourea and various acetoacetanilide derivatives in ethanol at 100 °C. In this protocol, taurine was used as a green and reusable bio-organic catalyst. Twenty-three novel derivatives of (R/S)-TDHPM-5-carboxanilides and their structures were confirmed by various spectroscopy techniques. The aforementioned compounds were synthesized via the formation of one asymmetric centre, one new C–C bond, and two new C–N bonds in the final product. All the newly synthesized compounds were obtained in their racemic form with up to 99% yield. In addition, the separation of the racemic mixture of all the newly synthesized compounds was carried out by chiral HPLC (Prep LC), which provided up to 99.99% purity. The absolute configuration of all the enantiomerically pure isomers was determined using a circular dichroism study and validated by a computational approach. With up to 99% yield of 4d, this one-pot synthetic approach can also be useful for large-scale industrial production. One of the separated isomers (4R)-(+)-4S developed as a single crystal, and it was found that this crystal structure was orthorhombic

A green bio-organic catalyst (taurine) promoted one-pot synthesis of (R/S)-2-thioxo-3,4-dihydropyrimidine(TDHPM)-5-carboxanilides: chiral investigations using circular dichroism and validation by computational approaches

Owing to the massive importance of dihydropyrimidine (DHPMs) scaffolds in the pharmaceutical industry and other areas, we developed an effective and sustainable one-pot reaction protocol for the synthesis of (R/S)-2-thioxo-DHPM-5-carboxanilides via the Biginelli-type cyclo-condensation reaction of aryl aldehydes, thiourea and various acetoacetanilide derivatives in ethanol at 100 °C. In this protocol, taurine was used as a green and reusable bio-organic catalyst. Twenty-three novel derivatives of (R/S)-TDHPM-5-carboxanilides and their structures were confirmed by various spectroscopy techniques. The aforementioned compounds were synthesized via the formation of one asymmetric centre, one new C–C bond, and two new C–N bonds in the final product. All the newly synthesized compounds were obtained in their racemic form with up to 99% yield. In addition, the separation of the racemic mixture of all the newly synthesized compounds was carried out by chiral HPLC (Prep LC), which provided up to 99.99% purity. The absolute configuration of all the enantiomerically pure isomers was determined using a circular dichroism study and validated by a computational approach. With up to 99% yield of 4d, this one-pot synthetic approach can also be useful for large-scale industrial production. One of the separated isomers (4R)-(+)-4S developed as a single crystal, and it was found that this crystal structure was orthorhombic