A Novel Mithramycin Analogue with High Antitumor Activity and Less Toxicity Generated by Combinatorial Biosynthesis

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• 作者：Luz E. N煤帽ez ; Stephen E. Nybo ; Javier Gonz谩lez-Sab铆n ; Mar铆a P茅rez ; Nuria Men茅ndez ; Alfredo F. Bra帽a ; Khaled A. Shaaban ; Min He ; Francisco Mor铆s ; Jos茅 A. Salas ; J眉rgen Rohr ; Carmen M茅ndez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 28, 2012
• 年：2012
• 卷：55
• 期：12
• 页码：5813-5825
• 全文大小：625K
• 年卷期：v.55,no.12(June 28, 2012)
• ISSN：1520-4804

文摘

Mithramycin is an antitumor compound produced by Streptomyces argillaceus that has been used for the treatment of several types of tumors and hypercalcaemia processes. However, its use in humans has been limited because of its side effects. Using combinatorial biosynthesis approaches, we have generated seven new mithramycin derivatives, which differ from the parental compound in the sugar profile or in both the sugar profile and the 3-side chain. From these studies three novel derivatives were identified, demycarosyl-3D-尾-d-digitoxosylmithramycin SK, demycarosylmithramycin SDK, and demycarosyl-3D-尾-d-digitoxosylmithramycin SDK, which show high antitumor activity. The first one, which combines two structural features previously found to improve pharmacological behavior, was generated following two different strategies, and it showed less toxicity than mithramycin. Preliminary in vivo evaluation of its antitumor activity through hollow fiber assays, and in subcutaneous colon and melanoma cancers xenografts models, suggests that demycarosyl-3D-尾-d-digitoxosylmithramycin SK could be a promising antitumor agent worthy of further investigation.