Synthesis and Anticancer Activity of Mitotic-Specific 3,4-Dihydropyridine-2(1H)-thiones

Abstract

Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine aalog (S1) were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity. Structure-activity relationship analysis of the compounds against a panel of cancer cell lines allowed to select a compound with a thiophene ring at C5 of a 3,4-dihydropyridine-2(1H)-thione (S22) with promising antiproliferative activity (IC50 equal 1.71 ± 0.58 µM) and selectivity (SI = 21.09) against melanoma A375 cells. Moreover, all three of the most active compounds from the antiproliferative study, namely S1, S19 and S22 showed better selectivity against A375 cells than reference drug, suggesting their possible lower toxicity and wider therapeutic index. As further study revealed, selected compounds inhibited tubulin polymerization via colchicine binding site in dose dependent manner, leading to aberrant mitotic spindle formation, cell cycle arrest and apoptosis. Summarizing, the current study showed that among obtained mitotic-specific inhibitors analogue with thiophene ring showed the highest antiproliferative activity and selectivity against cancer cells.

Exploring the antitumor potential of novel quinoline derivatives via tubulin polymerization inhibition in breast cancer; design, synthesis and molecular docking

“…3). [20][21][22][23][24][25][26] Quinoline is a privileged scaffold in the expansion of anticancer drugs as they have exhibited potent antiproliferative activity via different mechanisms of action including cell cycle arrest, induction of apoptosis, and inhibition of angiogenesis, and cell migration disruption. Many tubulin inhibitors IX-XIV also, possess quinoline motifs (Fig.…”

Microwave‐Assisted Synthesis of 4‐Aryl‐1,4‐dihydropyridines as Potent Anticancer Agent and Their In‐Silico Studies

“…[1][2][3] The dihydropyridine group consists of numerous drugs with diverse pharmacokinetic profiles and biological practices and responses. [4,5] They have attracted a lot of interest due to their significant biological applications such as antitumor, antihypertensive, anticonvulsant, cytotoxic, and significant analgesic activities. [6][7][8][9] Dihydropyridines are well known for their calcium channel blocking activity.…”

“…Dihydropyridine derivatives have occupied a prominent place in medicinal chemistry because of their success as a central core in many drugs and are known for their multi‐receptor affinities with targeted enzymes [1–3] . The dihydropyridine group consists of numerous drugs with diverse pharmacokinetic profiles and biological practices and responses [4,5] . They have attracted a lot of interest due to their significant biological applications such as antitumor, antihypertensive, anticonvulsant, cytotoxic, and significant analgesic activities [6–9] .…”