Marine natural products: chemical and biological potential of seaweeds and their endophytic fungi

Marine natural products have currently been recognized as the most promising source of bioactive substances for drug discovery research. In this review, extraordinary metabolites from marine algae species are illustrated, as well as approaches for their isolation and determination of their biological properties and pharmaceutical potential. Furthermore, marine endophytic microorganisms (from marine algae) are presented as a new subject for extensive investigation to find novel natural products, which make them a potentially rich and innovative source for new drug candidates.

Natural products as leads for anticancer drug discovery: discovery of new chemotypes of microtubule stabilizers through reengineering of the epothilone scaffold

Epothilones are bacterial macrolides with potent microtubule-stabilizing and antiproliferative activity, which have served as successful lead structures for the discovery of several clinical candidates for cancer treatment. Overall, seven epothilone-type agents have been advanced to clinical evaluation in humans so far and one of these has been approved by the FDA in 2007 for clinical use in breast cancer patients. Notwithstanding these impressive numbers, however, the structural diversity represented by the collection of epothilone analogs that have been (or still are) investigated clinically is rather limited and their individual structures show little divergence from the original natural product leads. In contrast, we have elaborated a series of epothilone-derived macro-lactones, whose overall structural features significantly deviate from those of the natural epothilone scaffold and thus define new structural families of microtubule-stabilizing agents. Key elements of our hypermodification strategy are the change of the natural epoxide geometry from cis to trans, the incorporation of conformationally constrained side chains, the removal of the C(3)-hydroxyl group, and the replacement of C(12) with nitrogen. The latter modification leads to aza-macrolides that may be described as 'non-natural natural products'.

Anticancer drugs from nature--natural products as a unique source of new microtubule-stabilizing agents

This review article provides an overview on the current state of research in the area of microtubule-stabilizing agents from natural sources, with a primary focus on the biochemistry, biology, and pharmacology associated with these compounds. A variety of natural products have been discovered over the last decade to inhibit human cancer cell proliferation through a taxol-like mechanism. These compounds represent a whole new range of structurally diverse lead structures for anticancer drug discovery.

Structural analogues of the natural products magnolol and honokiol as potent allosteric potentiators of GABA(A) receptors.

Biphenylic compounds related to the natural products magnolol and 4'-O-methylhonokiol were synthesized, evaluated and optimized as positive allosteric modulators (PAMs) of GABA(A) receptors. The most efficacious compounds were the magnolol analog 5-ethyl-5'-hexylbiphenyl-2,2'-diol (45) and the honokiol analogs 4'-methoxy-5-propylbiphenyl-2-ol (61), 5-butyl-4'-methoxybiphenyl-2-ol (62) and 5-hexyl-4'-methoxybiphenyl-2-ol (64), which showed a most powerful potentiation of GABA-induced currents (up to 20-fold at a GABA concentration of 3μM). They were found not to interfere with the allosteric sites occupied by known allosteric modulators, such as benzodiazepines and N-arachidonoylglycerol. These new PAMs will be useful as pharmacological tools and may have therapeutic potential for mono-therapy, or in combination, for example, with GABA(A) receptor agonists.

Phylogenomic analysis of natural products biosynthetic gene clusters allows discovery of arseno-organic metabolites in model streptomycetes

We are indebted with Marnix Medema, Paul Straight and Sean Rovito, for useful discussions and critical reading of the manuscript, as well as with Alicia Chagolla and Yolanda Rodriguez of the MS Service of Unidad Irapuato, Cinvestav, and Araceli Fernandez for technical support in high-performance computing. This work was funded by Conacyt Mexico (grants No. 179290 and 177568) and FINNOVA Mexico (grant No. 214716) to FBG. PCM was funded by Conacyt scholarship (No. 28830) and a Cinvestav posdoctoral fellowship. JF and JFK acknowledge funding from the College of Physical Sciences, University of Aberdeen, UK.

Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel “unnatural” natural products

The structures of complex polyketide natural products, such as erythromycin, are programmed by multifunctional polyketide synthases (PKSs) that contain modular arrangements of functional domains. The colinearity between the activities of modular PKS domains and structure of the polyketide product portends the generation of novel organic compounds—“unnatural” natural products—by genetic manipulation. We have engineered the erythromycin polyketide synthase genes to effect combinatorial alterations of catalytic activities in the biosynthetic pathway, generating a library of >50 macrolides that would be impractical to produce by chemical methods. The library includes examples of analogs with one, two, and three altered carbon centers of the polyketide products. The manipulation of multiple biosynthetic steps in a PKS is an important milestone toward the goal of producing large libraries of unnatural natural products for biological and pharmaceutical applications.

A supplement to The chemistry of natural products related to phenanthrene /

"A reprint of the Appendix of recent literature (to the publication date, January 1, 1937), and revised indexes with page references to the First Edition."

The chemistry of natural products related to phenanthrene,

Blank pages for "Memoranda" ([10] at end)

Marine isocyanides and related natural products structure, biosynthesis and ecology

This review highlights structural and biosynthetic work on a group of nitrogen-functionalised terpenes that are almost exclusively found in marine invertebrates and the animals that feed on them. The chemical functionality reviewed includes isocyanides, isothiocyanates, formamides, thiocyanates, isocyanates, and dichloroimines. The literature through mid 2003 is reviewed and there are 143 citations.