A Bis-benzopyrroloisoquinoline Alkaloid Incorporating a Cyclobutane Core and a Chlorophenanthroindolizidine Alkaloid with Cytotoxic Activity from Ficus fistulosa var. tengerensis

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2017-10, Vol.80 (10), p.2734-2740
• Main Authors: Al-Khdhairawi, Amjad Ayad Qatran, Krishnan, Premanand, Mai, Chun-Wai, Chung, Felicia Fei-Lei, Leong, Chee-Onn, Yong, Kien-Thai, Chong, Kam-Weng, Low, Yun-Yee, Kam, Toh-Seok, Lim, Kuan-Hon
• Format: Article
• Language: English
• Subjects: Alkaloids - chemistry; Alkaloids - isolation & purification; Alkaloids - pharmacology; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Breast Neoplasms - drug therapy; Crystallography, X-Ray; Cyclobutanes - chemistry; Cyclobutanes - isolation & purification; Cyclobutanes - pharmacology; Ficus - chemistry; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - isolation & purification; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Indolizines - chemistry; Inhibitory Concentration 50; Isoquinolines; Malaysia; Molecular Conformation; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Phenanthrolines - chemistry; Plant Leaves - chemistry; Stereoisomerism
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.7b00500

Tengerensine (1), isolated as a racemate and constituted from a pair of bis-benzopyrroloisoquinoline enantiomers, and tengechlorenine (2), purified as a scalemic mixture and constituted from a pair of chlorinated phenanthroindolizidine enantiomers, were isolated from the leaves of Ficus fistulosa var. tengerensis, along with three other known alkaloids. The structures of 1 and 2 were determined by spectroscopic data interpretation and X-ray diffraction analysis. The enantiomers of 1 were separated by chiral-phase HPLC, and the absolute configurations of (+)-1 and (−)-1 were established via experimental and calculated ECD data. Compound 1 is notable in being a rare unsymmetrical cyclobutane adduct and is the first example of a dimeric benzopyrroloisoquinoline alkaloid, while compound 2 represents the first naturally occurring halogenated phenanthroindolizidine alkaloid. Compound (+)-1 displayed a selective in vitro cytotoxic effect against MDA-MB-468 cells (IC50 7.4 μM), while compound 2 showed pronounced in vitro cytotoxic activity against all three breast cancer cell lines tested (MDA-MB-468, MDA-MB-231, and MCF7; IC50 values of 0.038–0.91 μM).