Docking, Synthesis and Antiproliferative Activity of N-Acylhydrazone Derivatives Designed as Combretastatin A4 Analogues

Abstract

Cancer is the second most common cause of death in the USA. Among the known classes of anticancer agents, the microtubule-targeted antimitotic drugs are considered to be one of the most important. They are usually classified into microtubule-destabilizing (e.g., Vinca alkaloids) and microtubule-stabilizing (e.g., paclitaxel) agents. Combretastatin A4 (CA-4), which is a natural stilbene isolated from Combretum caffrum, is a microtubule-destabilizing agent that binds to the colchicine domain on β-tubulin and exhibits a lower toxicity profile than paclitaxel or the Vinca alkaloids. In this paper, we describe the docking study, synthesis, antiproliferative activity and selectivity index of the N-acylhydrazone derivatives (5a–r) designed as CA-4 analogues. The essential structural requirements for molecular recognition by the colchicine binding site of β-tubulin were recognized, and several compounds with moderate to high antiproliferative potency (IC50 values ≤18 µM and ≥4 nM) were identified. Among these active compounds, LASSBio-1586 (5b) emerged as a simple antitumor drug candidate, which is capable of inhibiting microtubule polymerization and possesses a broad in vitro and in vivo antiproliferative profile, as well as a better selectivity index than the prototype CA-4, indicating improved selective cytotoxicity toward cancer cells.

The Influence of Process Energy on the Yield of Asymmetric Curcumin Analog from Cullilawan Oil

“…An intermediate product 3-Benzo [1,3]dioxol-5-yl-propenal obtained from condensation piperonal reaction with acetaldehyde having yield 70.28 % .Time retention 12.43 minutes to an intermediate product with purity 23.59 % showed compound with the molecular weight of 176 g/mol. The product that has the highest concentration in the retention 9,58 minute is piperonal who had not participated in react.…”

“…The product that has the highest concentration in the retention 9,58 minute is piperonal who had not participated in react. Synthesis of compounds 3-benzo [1,3]dioxol-5-yl-propenal based on Claisen-Schmidt reaction involving two stages reaction. The first stage is an addition reaction nucleophile stage.…”

“…Cancer is the second most common cause of death in the world [1] and breast cancer is the leading cause of death in women due to metastasis of the cancer [2]. Proven natural ingredients as anticancer are curcumin [3,4], curcumin analogues [5,6].…”

“…Asymmetric curcumin analogue (5-benzo [1,3] dioxol-5-yl-1-phenyl-penta-2,4-dien-1-one) is a curcumin analog compound synthesized from culilawan oil using several stages of the reaction. The curcumin analog compound is obtained from the condensation reaction between the intermediate product (3-Benzo [1,3] dioxol-5-yl-propenal) and acetophenone under alkaline conditions [14].…”

“…The curcumin analog compound is obtained from the condensation reaction between the intermediate product (3-Benzo [1,3] dioxol-5-yl-propenal) and acetophenone under alkaline conditions [14]. The cytotoxic activity of the compound is also affected by the process method, in which thermodynamic control affects the product.…”