Elsevier

Tetrahedron

Volume 67, Issue 51, 23 December 2011, Pages 9950-9956
Tetrahedron

Syntheses and cytotoxicity of syringolin B-based proteasome inhibitors

Dedicated to Professor Gilbert Stork in honor of his 90th birthday, and in appreciation of his many decades of contributions to good chemistry and good humor
https://doi.org/10.1016/j.tet.2011.09.048Get rights and content

Abstract

The concise and modular total synthesis of the bacterial natural product and irreversible proteasome inhibitor syringolin B has been achieved. This synthesis has enabled the ready preparation of three diverse, structurally modified syringolin derivatives. The actions of these compounds in inhibiting the proliferation of neuroblastoma cell lines was evaluated, and significant enhancements in potency compared to the natural product were realized.

Introduction

The inhibition of protein degradation via the ubiquitin-proteasome system has recently been recognized as a useful mode of action for novel drugs.1 One such FDA-approved drug, a boronic acid peptide analog called bortezomib, is used in the treatment of refractory multiple myeloma and mantle cell lymphoma. However, it has significant side effects (such as neuropathy), not all patients respond to it, and many responders eventually develop resistance.2 Consequently, second-generation proteasome inhibitors are being actively sought, one approach being based on natural products. Many such compounds have been discovered, almost all inactivating the proteasome by reacting with it covalently. Two have entered clinical trials against multiple myeloma: a Phase 1 study of salinosporamide A is complete, and a Phase 2 study of carfilzomib, a modified version of two natural products, eponemycin and epoxomicin, achieved a significant response.3

This work focuses on a family of bacterial 12-membered lactam proteasome inhibitors called the syrbactins (Fig. 1). They include the syringolins,4 glidobactins,5 and cepafungins,6 all of which express at least some anticancer activity. Their mode of action is via the conjugate addition of a proteasome hydroxyl group to the α,β-unsaturated amide. Among the natural proteasome inhibitors, the syrbactins provide an especially attractive starting point for therapeutic development because they can be synthesized in a relatively concise fashion. In addition to a classical synthesis of glidobactin A,7 three total syntheses of syringolin A have been recently reported,8 including our own;9 Kaiser’s lab and ours have also prepared syringolin B. Considerable follow-on work on the biological properties of syringolin derivatives has emerged from Kaiser and Bachmann.10 A specific feature sought in our studies was a modular synthetic approach with potential for the preparation of structural variants by the substitution of modules, the concept of diversity-oriented synthesis.11 Syringolin B is an appealing platform for a synthesis-based program toward novel proteasome inhibitors because a large portion of its structure is based on lysine, and many lysine analogs can be readily accessed. Here, we describe in full detail the total synthesis of syringolin B, the preparation of several structural variants, and their initial biological screening.

Section snippets

Total synthesis

The key to our approach to the syrbactins was the creation of the α,β-unsaturated 12-membered macrolactam via an intramolecular Horner–Wadsworth–Emmons (HWE) reaction. This reaction has strong precedents for the formation of large rings in high efficiency, including some larger than 30 atoms,12 whereas other syrbactin syntheses have suffered from significant difficulties in closure of the large ring (15–49% yields).

The synthesis of syringolin B (Scheme 1) involves seven steps from the

Discussion

The total synthesis of syringolin B described here is brief, efficient, versatile, and amenable to diversity-oriented synthesis. This versatility was demonstrated through the preparation of three syringolin B relatives with changes in the side chain and two of the three sub-segments of the macrolactam. The preparation of these analogs revealed areas for further research on syrbactin synthesis. More reliable approaches to side-chain attachment are surely needed, and better methods to permit the

General

All melting points were measured on a Büchi Melting Point B-545 and are uncorrected. 1H and 13C NMR spectra were recorded on Varian Inova 300 (300 MHz and 75 MHz, respectively) or Varian Inova 400 (400 MHz and 100 MHz, respectively) as noted, are internally referenced to residual solvent signals, and are expressed in parts per million (ppm). IR spectra were recorded on a Perkin–Elmer Spectrum One FT-IR spectrometer using the ATR accessory. Mass spectra were obtained in the UCR Analytical

Acknowledgements

We are grateful to Pat Clay and Dr. Paul Silverman at Valent Biosciences for gifts of aminoethoxyvinylglycine. Erin Mitsunaga is thanked for her initial contributions to this project. Financial support was provided by UC-MEXUS and CONACYT (postdoctoral fellowships to T.R.I.-R.), the University of California Cancer Research Coordinating Committee (M.C.P.), and the Hawaii Community Foundation HCF Perry fund grant 10ADVC-47862 to A.S.B.

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Present address: Department of Analytical Chemistry, Autonomous University of Nuevo León, Monterrey, Mexico.

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