Total Synthesis and Comparative Evaluation of Luzopeptin A-C and Quinoxapeptin A-C

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• 作者：Dale L. Boger ; Mark W. Ledeboer ; Masaharu Kume ; Mark Searcey ; and Qing Jin
• 刊名：Journal of the American Chemical Society
• 出版年：1999
• 出版时间：December 15, 1999
• 年：1999
• 卷：121
• 期：49
• 页码：11375 - 11383
• 全文大小：267K
• 年卷期：v.121,no.49(December 15, 1999)
• ISSN：1520-5126

文摘

Full details of the total syntheses of luzopeptin A-C and quinoxapeptin A-C, C₂-symmetric cyclicdepsidecapeptides bearing two pendant heterocyclic chromophores, are disclosed and serve to establish thequinoxapeptin relative and absolute configuration. Key elements of the approach include the late-stageintroduction of the chromophore and penultimate L-Htp acylation permitting the divergent synthesis of theluzopeptins, quinoxapeptins, and structural analogues from a common advanced intermediate. Symmetricalpentadepsipeptide coupling and macrocyclization of the 32-membered ring conducted at the single secondaryamide site provided the common cyclic decadepsipeptide. The convergent preparation of the requiredpentadepsipeptide with installation of the labile ester in the final coupling was achieved under surprisinglyeffective racemization-free conditions. The quinoxapeptins were shown to bind to DNA by high-affinitybisintercalation analogous to sandramycin and the luzopeptins. Significant similarities in the DNA binding ofsandramycin and luzopeptin A were observed, and these compounds proved distinguishable from thequinoxapeptins, indicating that the structural alterations in the chromophore impact the affinity and selectivitymore than the changes in the decadepsipeptide. The luzopeptins proved to be more potent cytotoxic agentsthan the corresponding quinoxapeptin, but the quinoxapeptins proved to be more potent inhibitors of HIV-1reverse transcriptase. In addition, a well-defined potency order was observed in the cytotoxic assays (A > B> C) in which the distinctions were extraordinarily large, with the removal of each L-Htp acyl substituentresulting in a 100-1000-fold reduction in potency. An equally well-defined but reverse potency order wasobserved in HIV-1 reverse transcriptase inhibition (C > B > A). Thus, the non-naturally occurring syntheticprecursor 6 (quinoxapeptin C) was found to exhibit the most potent HIV-1 reverse transcriptase inhibition inthe series and to lack a dose-limiting in vitro cytotoxic activity, making it the most attractive member of theseries examined.