Abstract
Cancer is one of the leading causes of death globally, accounting for an estimated 8 million deaths each year. As a result, there have been urgent unmet medical needs to discover novel oncology drugs. Natural and synthetic lactones have a broad spectrum of biological uses including anti-tumor, anti-helminthic, anti-microbial, and anti-inflammatory activities. Particularly, several natural and synthetic lactones have emerged as anti-cancer agents over the past decades. In this review, we address natural and synthetic lactones focusing on their anti-tumor activities and synthetic routes. Moreover, we aim to highlight our journey towards chemical modification and biological evaluation of a resorcylic acid lactone, L-783277 (4). We anticipate that utilization of the natural and synthetic lactones as novel scaffolds would benefit the process of oncology drug discovery campaigns based on natural products.
Highlights
Cancer, the second leading cause of death worldwide, has become one of the greatest challenges to global health
The pharmacologically significant natural products have been providing inspiration and guidance to make a paradigm shift for innovative drug development strategies, which serve as a great starting point for initiation of drug discovery programs
Taking into account the researches elucidated above, the natural and synthetic lactones addressed in this review strongly suggest that they are promising therapeutic leads for oncology drug discovery program
Summary
The second leading cause of death worldwide, has become one of the greatest challenges to global health. A synthesis of resorcylic acid macrolactam analogs of the natural product radicicol (1) is described in which the key steps are the acylation and ring opening of a homophthalic anhydride to give an isocoumarin, followed by a ring-closing metathesis to form the macrocycle. Bolic stability, regained full in vitro potency similar to natural product, and had significant improvement in in vivo potency (Scheme 17) Their synthesis started from commercially available methyl orsellinate (85) and after 5 steps afforded aromatic selenide intermediate 86 which was coupled with acyclic iodide in the presence of LiHMDS followed by mCPBA oxidation, TBAF deprotection, and lactone cyclization under the influen12coef 6o7f Mukaiyama’s reagent to provide lactone 87. SScchheemmee440.0S. ySnytnhtehsiessoisf roifgirdigifiidedifiaendalaongauleoogfuLe-7o8f3L27-78(312007)7b(y10S0im) beyt aSli.m[54e]t. al. [54]
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