Tailoring 3,3′-Dihydroxyisorenieratene to Hydroxystilbene: Finding a Resveratrol Analogue with Increased Antiproliferation Activity and Cell Selectivity

• Published in: Chemistry : a European journal 2014-07, Vol.20 (29), p.8904-8908
• Main Authors: Kang , Yan-Fei, Yan , Wen-Jing, Zhou , Ting-Wen, Dai, Fang, Li, Xiu-Zhuang, Bao, Xia-Zhen, Du, Yu-Ting, Yuan, Cui-Hong, Wang, Hai-Bo, Ren, Xiao-Rong, Liu, Qiang, Jin, Xiao-Ling, Zhou, Bo, Zhang, Jie
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - pharmacology; antiproliferation; Antiproliferatives; Blocking; Carotenoids; Carotenoids - chemistry; Carotenoids - pharmacokinetics; Carotenoids - pharmacology; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Drug Discovery; Humans; Isoprene; isoprene units; Mathematical analysis; methylation reactions; Models, Molecular; resveratrol; Stability; Stilbenes - chemistry; Stilbenes - pharmacokinetics; Stilbenes - pharmacology; Strategy; Uptakes
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201403024

Four novel compounds were designed by “tailoring” 3,3′‐dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 (2,3,6,2′,3′,6′‐hexamethyl‐4,4′‐dihydroxy‐trans‐stilbene) was concisely synthesized in a one‐pot Stille–Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity mediated by blocking the NCI‐H460 cell cycle in G1 phase. Additionally, theoretical calculations and cell uptake experiments indicate that the unique polymethylation pattern of compound 1 significantly induces a conformational change shift out of planarity and increases its cell uptake and metabolic stability. The observation should be helpful to rationally design resveratrol‐inspired antiproliferative agents. Four novel compounds were designed by “tailoring” 3,3′‐dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 was concisely synthesized by a one‐pot Stille–Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity (see figure).