Paper
Heterocyclization of 2-Arylidencyclohexan-1,3-dione: Synthesis of Thiophene, Thiazole and Isoxazole Derivatives with Potential Antitumor Activities.
Published 2019 · N. Y. M. Abdo, R. Mohareb, W. N. Al-darkazali
Anti-cancer agents in medicinal chemistry
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Abstract
BACKGROUND Thiophene, thiazole and isoxazole derivatives are present in a wide range of natural and synthetic compounds with heterogeneous pharmacological activity. Due to their structural diversity, they are one of the most versatile classes of compounds for anticancer drug design and discovery. OBJECTIVE Thiophene, thiazole and isoxazole derivatives were herein designed with a dual purpose: as antiproliferative agents and kinase inhibitions. METHODS The test compounds were synthesized in moderate to high yields through a simple methodology. Tetrahydrobenzo[b]thiophen-5-one derivatives 5a-f were prepared from the reaction of 2-arylidencyclohexan-1,3-dione 3a-c with elemental sulfur and either of malonanitrile (4a) or ethyl cyanoacetate (4b) in 1,4-dioxan in the presence of triethylamine. Compounds 5a,b were used for the synthesis of thiophene, thiazole and isoxazale derivatives through their reactions with different chemical reagents. RESULTS Antiproliferative evaluations, c-Met kinase and Pim-1 kinase inhibitions were performed where some compounds revealed high activities. In all cases, antiproliferative activity and the kinase inhibitions were performed against six cancer cell llines and five tyrosine kinases, respectively. Where the most cytotoxic compounds were 3c, 5d and 16c with IC50's 0.29, 0.68 and 0.42μM, respectively against A549 cell line. CONCLUSION The anti-proliferative activities of the newly synthesized compounds were evaluated against the six cancer cell lines (A549, HT-29, MKN-45, U87MG, SMMC-7721 and H460). The most potent compounds toward the cancer cell lines (3a, 3c, 5d, 7c, 11c, 16a and 16c) were further investigated towards the five tyrosine kinases (c-kit, FIT-3, VEGFR-2, EGFR and PDGFR). Compounds 3c, 5d and 16c were selected for testing of their inhibition for the Pim-1 kinase due to their anti-proliferation activities against the cancer cell lines and their high activities against the tyrosine kinases.
In Vitro StudyThiophene, thiazole, and isoxazole derivatives show potential antitumor activities and kinase inhibition, with compounds 3c, 5d, and 16c showing the most cytotoxic effects against cancer cell lines.
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