Discovery, Characterization, and Analogue Synthesis of Bohemamine Dimers Generated by Non-enzymatic Biosynthesis

• Published in: Chemistry : a European journal 2016-03, Vol.22 (10), p.3491-3495
• Main Authors: Fu, Peng, Legako, Aaron, La, Scott, MacMillan, John B.
• Format: Article
• Language: English
• Subjects: Aldehydes; Analogs; Aromatic compounds; Biosynthesis; Biotechnology; bohemamine; Cancer; Cell culture; Chemistry; Culture; Cytotoxicity; Dimerization; Dimers; Evaluation; Formaldehyde; Libraries; Lung cancer; marine-derived streptomyces; Methylene; non-enzymatic biosynthesis; Spectroscopic analysis; Synthesis; Toxicity
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201600024

Dibohemamines A–C (5–7), three new dimeric bohemamine analogues dimerized through a methylene group, were isolated from a marine‐derived Streptomyces spinoverrucosus. The structures determined by spectroscopic analysis were confirmed through the semi‐synthetic derivatization of monomeric bohemamines and formaldehyde. These reactions, which could occur under mild conditions, together with the detection of formaldehyde in the culture, revealed that this dimerization is a non‐enzymatic process. In addition to the unique dimerization of the dibohemamines, dibohemamines B and C were found to have nm cytotoxicity against the non‐small cell‐lung cancer cell line A549. In view of the potent cytotoxicity of compounds 6 and 7, a small library of bohemamine analogues was generated for biological evaluation by utilizing a series of aryl and alkyl aldehydes. A fortuitous dimerization: Three new dimeric bohemamine analogues dimerized through a methylene group were isolated from a marine‐derived Streptomyces spinoverrucosus. The dimers can be formed through the semi‐synthetic derivatization of monomeric bohemamines and formaldehyde under mild conditions. Furthermore, the formaldehyde could be detected in the culture. These results revealed that this dimerization is a non‐enzymatic process (see scheme).