Synthesis and Biological Evaluation of Analogues of Cryptolepine, an Alkaloid Isolated from the Suriname Rainforest

• Published in: Journal of natural products (Washington, D.C.) D.C.), 1999-07, Vol.62 (7), p.976-983
• Main Authors: Yang, Shu-Wei, Abdel-Kader, Maged, Malone, Stan, Werkhoven, Marga C. M, Wisse, Jan H, Bursuker, Isia, Neddermann, Kim, Fairchild, Craig, Raventos-Suarez, Carmen, Menendez, Ana T, Lane, Kate, Kingston, David G. I
• Format: Article
• Language: English
• Subjects: alkaloids; Alkaloids - chemical synthesis; Alkaloids - isolation & purification; Alkaloids - pharmacology; analogs; Antifungal Agents - isolation & purification; Antifungal Agents - pharmacology; Antineoplastic agents; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; biochemical pathways; Biological and medical sciences; biosynthesis; Cell Cycle - drug effects; chemical constituents of plants; chemical reactions; chemical structure; cytotoxic compounds; DNA Damage; dna modification; dna-damaging agents; Drug Screening Assays, Antitumor; drugs; General aspects; General pharmacology; Humans; Indole Alkaloids; Indoles; Medical sciences; medicinal plants; Microbial Sensitivity Tests; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Plants, Medicinal - chemistry; precursors; Quinolines; Rubiaceae; Saccharomyces cerevisiae - drug effects; Sapotaceae; spectral analysis; Suriname; Tumor Cells, Cultured
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np990035g

Bioassay-guided fractionation of an extract of a mixture of Microphilis guyanensis and Genipa americana collected in the rainforest of Suriname yielded the known alkaloid cryptolepine (2) as the major active compound in a yeast bioassay for potential DNA-damaging agents; the same compound was later reisolated from M. guyanensis. The structure of cryptolepine was identified unambiguously by spectral data and by its total synthesis. Several cryptolepine derivatives (3−29, 32−41) were synthesized based on modifications of the C-2, N-5, N-10, and C-11 positions. Two cryptolepine dimers (30, 31) were also prepared. The structure modifications did not result in compounds with a higher potency than the parent compound cryptolepine in the yeast assay system, although some derivatives did show significant activity. Selected compounds (6, 7, 17, 22, 23, 26, and 27) were also tested for cytotoxicity in mammalian cell culture, and two compounds showed significant cytotoxic activity.