A novel mithramycin analogue with high antitumor activity and less toxicity generated by combinatorial biosynthesis.

Abstract

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-β-d-digitoxosylmithramycin SK, demycarosylmithramycin SDK, and demycarosyl-3D-β-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-β-d-digitoxosylmithramycin SK could be a promising antitumor agent worthy of further investigation.

• Authors: Luz E Núñez, Stephen E Nybo, Javier González-Sabín, María Pérez, Nuria Menéndez, Alfredo F Braña, Khaled A Shaaban, Min He, Francisco Morís, José A Salas, Jürgen Rohr, Carmen Méndez
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 12 Pg. 5813-25 (Jun 28 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22578073 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Plicamycin

Topics

• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacology, toxicity)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy, pathology)
• Humans
• Melanoma (drug therapy, pathology)
• Mice
• Plicamycin (analogs & derivatives, biosynthesis, pharmacology, toxicity)
• Streptomyces (metabolism)
• Xenograft Model Antitumor Assays