“From Large-Scale Collections to the Potential Use of Genomic Techniques for Supply of Drug Candidates”

Abstract

The initial sources of marine-derived compounds that on a small scale exhibited interesting biological activities, were often confined to collection levels ranging from <100 grams to a kilogram. Then if significant interest was shown, collections on a larger scale were made of the nominal source organism. Due to many reasons, including but not limited to realization of the environmental harm that can occur, and in some cases, has occurred, over the last 15 plus years, the paradigm moved to semi-synthesis, total synthesis (sometimes of simpler versions) and the use of genomic techniques both to identify the "source" and then to utilize the data in due course. In this short review, examples of how ideas have changed will range from the early days with the arabinose-containing nucleosides, the sourcing and use of didemnins and their derivatives, work with bryostatins, ecteinascidins and halichondrins, and then demonstrate how molecules derived from dolastatins are now used as "warheads." In most cases the varying methods used will be discussed, albeit in brief in some cases, with the aim of demonstrating how various techniques were used to optimize these compounds and their derivatives. The review finishes with comments as to the current and future involvement of microbes as sources of these and other agents.

Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019

“…Since the last review, we have also published either together, independently, or with other authors a number of intermediate reports and/or standalone articles on natural products as drug leads or actual drugs. A partial listing includes the following: endophytic and epiphytic microbes as sources of bioactive natural products; − marine drug candidates; a chemometric analysis of the natural product drugs in the 2016 review versus synthetic drugs; a review of methods of “persuading” microbes to reveal their hidden genetic information; natural product scaffolds of value in drug discovery; a discussion on the value of marine-derived drugs; the influence of nucleosides and adrenergic agents on drug discovery; a discussion on the influence of Brazilian biodiversity on drug discovery covering the pederine-based drug candidates and the sources of ACE inhibitors; the screening of natural product extracts to identify complex 1 bypass factors; a review of currently uncultured microbes as sources of natural products; a chapter on biodiversity and drug discovery (in a Brazilian book); a review on marine-derived warheads for antitumor antibody–drug conjugates; a review on current screening methods to identify natural product-based compounds; a book chapter on microbial involvement in natural product production by organisms from all kingdoms; a requested review on bioactive cyclic molecules and drug design; a short discussion article on synthetic modifications of vancomycin structures to overcome resistance; a chapter on natural products as antitumor compounds; a chapter on pharmacological aspects of marine natural products, but not involving any antitumor agents; a discussion piece covering the “true producers” of natural products from microbial sources; a review discussing the use of both large-scale collections and genomic techniques with marine natural products; a chapter on extremophilic marine fungi; and a recent article on marine-derived agents as warheads in ADCs . All these articles demonstrate that natural product and/or natural product structures continued to play a highly significant role in the drug discovery and development process.…”

Fairness, Equity and Efficiency for the Convention on Biological Diversity and the Nagoya Protocol: Analysis of a Rodent, a Snail, a Sponge and a Virus. Part 2

“…For this reason, their presence in the habitat of the sponge has not been studied in depth. These new findings conclude that either T. crypta contains microbes which produce compounds of interest, or sequesters such compounds (Newman, 2018) The answers are as of yet unclear and require further investigation, perhaps utilizing not only samples of the species but also a detailed observation of the habitat.…”

“…An earlier paper published in the journal Molecular Cancer Therapies suggested that microorganisms, living in conjunction with sponges, are the true sources of many bioactive and useful constituents (Simmons et al, 2005, p. 335). Spongosine compounds are currently being used for novel drug development to treat inflammation and pain (Newman, 2018;Bertin et al 2015).…”

Chemical Investigations of Pacific Marine Organisms

“…291 Didemnin B was the first marine metabolite to acquire attention from the synthetic community to supply preclinical and clinical trials, but was abandoned during early Phase II trials owing to significant toxicity. 292 Its dehydro derivative, plitidepsin (14), was mentioned in Chapter 1 as the second tunicate-derived drug, approved for treatment of multiple myeloma in 2018. 50 The pyridoacridone alkaloids 144 and 145, related to ascididemin (146), were isolated from the NZ tunicate Lissoclinum notti and showed anti-TB activity against M. tuberculosis H37Rv but no significant cytotoxicity.…”