Design, synthesis and 3D-QSAR of β-carboline derivatives as potent antitumor agents

• Published in: European journal of medicinal chemistry Vol. 45; no. 6; pp. 2503 - 2515
• Main Authors: Cao, Rihui, Guan, Xiangdong, Shi, Buxi, Chen, Zhiyong, Ren, Zhenhua, Peng, Wenlie, Song, Huacan
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.06.2010; Elsevier
• Subjects: 3D-QSAR; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor; Biological and medical sciences; Carbolines - chemistry; Carbolines - pharmacology; Cell Line, Tumor; Chemistry, Medicinal; Drug Design; General aspects; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Conformation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Quantitative Structure-Activity Relationship; Science & Technology; Synthesis; β-Carboline; 3D-QSAR; β-Carboline; Synthesis; Antitumor; CYTOTOXIC ACTIVITIES; BRAIN BENZODIAZEPINE RECEPTORS; ANALOGS; beta-Carboline; HUMAN MONOAMINE-OXIDASE; IN-VITRO; ANTITHROMBOTIC ACTIVITY; INHIBITORS; BINDING; ALKALOIDS; HARMINE; Antineoplastic agent; Stomach; Organic cation; Liver; Prediction; Cytotoxicity; Uterine cervix; In vitro; Modeling; Tissue; Three dimensional model; Comparative molecular similarity indices analysis method; Structure activity relation; Molecular model; Comparative molecular field analysis method; Mammary gland; Chemical synthesis; Tumor cell
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.02.036

In a continuing effort to develop novel β-carbolines endowed with better pharmacological profiles, a series of β-carboline derivatives were designed and synthesized based on the previously developed SARs. Cytotoxicities in vitro of these compounds against a panel of human tumor cell lines were also investigated. The results demonstrated that the N 2-benzylated β-carbolinium bromides 56– 60 represented the most potent compounds with IC 50 values lower than 10 μM. The application of 3D-QSAR to these compounds explored the structural basis for their biological activities. CoMFA ( q 2 = 0.513, r 2 = 0.862) and CoMSIA ( q 2 = 0.503, r 2 = 0.831) models were developed for a set of 47 β-carbolines. The results indicated that the antitumor pharmacophore of these molecules were marked at position-1, -2, -3, -7 and -9 of β-carboline ring. The constructive CoMFA and CoMSIA models with highly predictive capacity provided important structural requirement for further design and synthesis of new β-carboline derivatives as potent antitumor agents. [Display omitted]