Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, 33006 Oviedo, Spain.
J Med Chem. 2012 Jun 28;55(12):5813-25. doi: 10.1021/jm300234t. Epub 2012 Jun 7.
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.
密曲霉素是一种由灰绿链霉菌产生的抗肿瘤化合物，已被用于治疗多种类型的肿瘤和高钙血症。然而，由于其副作用，其在人类中的应用受到限制。通过组合生物合成方法，我们生成了七个新的密曲霉素衍生物，它们在糖谱或糖谱和 3-侧链方面与母体化合物不同。从这些研究中鉴定出三种新型衍生物，即脱甲酰基-3D-β-d-地高辛基密曲霉素 SK、脱甲酰基密曲霉素 SDK 和脱甲酰基-3D-β-d-地高辛基密曲霉素 SDK，它们具有高抗肿瘤活性。第一个结合了先前发现的两种改善药理行为的结构特征，是通过两种不同的策略生成的，其毒性比密曲霉素低。通过空心纤维测定法和皮下结肠癌和黑色素瘤异种移植模型进行的初步体内抗肿瘤活性评估表明，脱甲酰基-3D-β-d-地高辛基密曲霉素 SK 可能是一种很有前途的抗肿瘤药物，值得进一步研究。
