Elsevier

Tetrahedron

Volume 58, Issue 32, 5 August 2002, Pages 6373-6380
Tetrahedron

Efficient relay syntheses and assessment of the DNA-cleaving properties of the pyrrole alkaloid derivatives permethyl storniamide A, lycogalic acid A dimethyl ester, and the halitulin core

This paper is dedicated to Professor Yoshito Kishi in recognition of his outstanding contributions to modern organic chemistry and natural product synthesis
https://doi.org/10.1016/S0040-4020(02)00637-3Get rights and content

Abstract

Palladium catalyzed Suzuki- and Negishi cross coupling reactions are used to convert the now readily available 3,4-dibromopyrrole derivatives 13 and 26 into the core structures of different pyrrole alkaloids. Several compounds of this series exhibit respectable cytotoxicity and resensitize multidrug resistant (MDR) cancer cell lines at non-toxic concentrations. Cytotoxicity and MDR reversal can be efficiently uncoupled by per-O-methylation of the peripheral hydroxyl groups. For the storniamide core structure 9 it is demonstrated that this chemical modification goes hand in hand with a complete loss of the DNA-cleaving capacity of the alkaloid.

Introduction

The ability of malignant cell lines to develop resistance against approved anticancer agents constitutes a major problem for efficient chemotherapy. This phenotype of multidrug resistance (MDR) is frequently caused by the overexpression of the plasma membrane glycoprotein P-gp which functions as an ATP-dependent pump able to export a wide variety of drugs out of mammalian cells, thus lowering their intramolecular concentration below the cytotoxic threshold.1 Agents that either retain activity on MDR cells or resensitize them by specifically interfering with the P-gp mediated efflux are needed to improve prognosis for patients failing to respond to conventional chemotherapy.

In this context, a series of marine alkaloids consisting of a pyrrole core surrounded by a periphery of polyoxygenated phenyl rings such as 18 (and many congeners) has recently attracted considerable attention.2., 3. They have been isolated from widely varying locations and organisms (ascidians, molluscs, sponges) and apparently derive from tyrosine or DOPA metabolism. Interestingly, exhaustive O-methylation of the lateral hydroxyl groups significantly reduces the cytotoxicity of these compounds but leaves the capacity for MDR reversal virtually unchanged.3 Thus, permethyl storniamide 8 (R=Me) as a prototype example exhibits essentially no cytotoxic activity against four different cancer cell lines (IC50>100 μM) but completely reverses MDR at 1 μM concentration, thus being more potent than the reference compound verapamil. Even more strikingly, the resistant human colon cancer cell line HTC116/VM46 becomes hypersensitive to doxorubicin and vincristine on treatment with 7.5 μM solutions of compound 9 representing the permethylated storniamide core region.3

Insights into the molecular mechanism of action of such pyrrole alkaloids, however, are still missing and no explanation as to why simple ether formation uncouples their cytotoxicity and MDR reversing capacity has been reported to date. Described below is a preliminary study showing that the nature of the peripheral –OR groups determines the ability of such alkaloids to interact with double stranded DNA. Whereas the storniamide core 10 containing free –OH groups at the rim constitutes a very potent strand cleaving agent, its –OMe congener 9 causes no damage under otherwise identical conditions.

Section snippets

Syntheses

Following the first total syntheses of lukianol A and lamellarin O dimethyl ether based on a titanium-mediated oxo-amide coupling reaction,4., 5. various imaginative approaches to alkaloids belonging to the lukianol-,6 lamellarin-,7 storniamide-,8 ningalin-9 and related families10 have been reported in the literature.11 Herein we describe a streamlined synthesis of the particularly promising compound 9 which is flexible enough to provide analogues as well. In view of its symmetrical core

General

All reactions were carried out under Ar. The solvents used were purified by distillation over the drying agents indicated and were transferred under Ar: THF, Et2O, DME (Mg–anthracene), CH2Cl2 (P4O10), MeCN, Et3N, pyridine, DMF (CaH2), MeOH (Mg), hexane, toluene (Na/K). Flash chromatography: Merck silica gel 60 (230–400 mesh). NMR: spectra were recorded on a Bruker DPX 300 spectrometer in the solvents indicated; chemical shifts (δ) are given in ppm relative to TMS, coupling constants (J) in Hz.

Acknowledgements

Generous financial support by the Deutsche Forschungsgemeinschaft (Leibniz award to A. F.) and by the Fonds der Chemischen Industrie is gratefully acknowledged. We thank Dr C. W. Lehmann for solving the X-ray structure of compound 14.

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