Potential Value of Plants as Sources of New Antifertility Agents II

The 90-kDa heat-shock protein (Hsp90) is a molecular chaperone responsible for the stability and function of a wide variety of client proteins that are critical for cell growth and survival. Many of these client proteins are frequently mutated and/or overexpressed in cancer cells and are therefore being actively pursued as individual therapeutic targets. Consequently, Hsp90 inhibition offers a promising strategy for simultaneous degradation of several anticancer targets. Currently, most Hsp90 inhibitors under clinical evaluation act by blocking the binding of ATP to the Hsp90 N-terminal domain and thereby, induce the degradation of many Hsp90-dependent oncoproteins. Although, they have shown some promising initial results, clinical challenges such as induction of the heat-shock response, retinopathy, and gastrointestinal tract toxicity are emerging from human trials, which constantly raise concerns about the future development of these inhibitors. Novobiocin derivatives, which do not bind the chaperone's N-terminal ATPase pocket, have emerged over the past decade as an alternative strategy to inhibit Hsp90, but to date, no derivative has been investigated in the clinical setting. In recent years, a number of natural or synthetic compounds have been identified that modulate Hsp90 function via various mechanisms. These compounds not only offer new chemotypes for the development of future Hsp90 inhibitors but can also serve as chemical probes to unravel the biology of Hsp90. This chapter presents a synopsis of inhibitors that directly, allosterically, or even indirectly alters Hsp90 function, and highlights their proposed mechanisms of action.

/pdf/anticancer-inhibitors-of-hsp90-function-beyond-the-usual-1wom0gh6bs.pdf

Anticancer Inhibitors of Hsp90 Function: Beyond the Usual Suspects.

Phenolic compounds from the fruit of Garcinia dulcis.

A benzil and isoflavone derivatives from Derris scandens Benth.

Over the past 150 years, since Vogel in 1820 isolated the parent oxygen heterocycle, coumarin (1) from Coumarouna odorata = Dipteryx odorata (1), coumarins have been recognized as widely distributed plant products. The vast majority carry an oxygen substituent at C-7; consequently 7-hydroxycoumarin [umbelliferone, (2)], one of the most widely distributed coumarins, is often regarded as the parent, in a structural sense and also biogenetically, of a large number of the structurally more complex coumarins. A number of review articles on natural plant coumarins have appeared (154, 302, 344, 420, 525, 541, 548) since the last in this series (153), the most comprehensive, albeit dealing solely with coumarins of the Umbelliferae, being that of Nielsen in 1970 (419).

Naturally Occurring Plant Coumarins

The root material of Derris robusta has yielded nine natural products whose structures have been determined mainly by physical methods in association with a few partial syntheses and degradations. Four of these have been shown to be new natural isoflavones: derrustone (II), derrubone (IIIa), robustone (VIa), and robustone methyl ether (VIb). The other five compounds are derivatives of the 3-aryl-4-hydroxycoumarin type, and include derrusnin (VIIb), robustic acid (IXa), robustic acid methyl ether (IXb), robustin (XIIa), and robustin methyl ether (XIIb). These 3-aryl-4-hydroxy(or methoxy)coumarins are variants upon the isoflavonoid theme. The pattern relating the structures of these co-occurring isoflavones and 3-aryl-4-oxycoumarins indicates that the biosyntheses of these two natural product types probably have many common features.

A. J. East

Papers

Natural occurrence of 3-aryl-4-hydroxycoumarins. Part I. Phytochemical examination of Derris robusta(roxb.) benth.