pederin and psymberin

This review highlights the broad range of science that has arisen from the isolation of pederin, the mycalamides, theopederins, and onnamides, and psymberin. Specific topics include structure determination, biological activity, synthesis, and analog preparation and analysis.

Topics: Animals; Antineoplastic Agents; Biological Products; Chemistry, Pharmaceutical; Coleoptera; Coumarins; Drug Screening Assays, Antitumor; Leukemia P388; Molecular Structure; Porifera; Pyrans; Pyrones; Structure-Activity Relationship

The mycalamide class of potent antiviral and antitumor natural compounds originally isolated from marine sponges in 1988 is a new interdisciplinary approach to molecular recognition. We review new synthetic approaches to this new family of natural products with remarkable biological activity. Some biological evaluation data are compiled and compared to other structurally similar molecular targets.

Topics: Animals; Antineoplastic Agents; Biological Products; Chemistry Techniques, Synthetic; Coleoptera; Coumarins; Humans; Neoplasms; Porifera; Pyrans

Two synthetic approaches to psymberin have been accomplished. A highly convergent first generation synthesis led to the complete stereochemical assignment and demonstrated that psymberin and irciniastatin A are identical compounds. This synthesis featured a diastereoselective aldol coupling between the aryl fragment and a central tetrahydropyran core and a novel one-pot procedure to convert an amide, via intermediacy of a sensitive methyl imidate, to the N-acyl aminal reminiscent of psymberin. The highlights of the second generation synthesis include an efficient iridium-catalyzed enantioselective bisallylation of neopentyl glycol and a stepwise Sonogashira coupling/cycloisomerization/reduction sequence to construct the dihydroisocoumarin unit. The two synthetic avenues were achieved in 17-18 steps (longest linear sequence, ~14-15 isolations) from 3 fragments prepared in 7-8 (first generation) and 3-8 (second generation) steps each. This convergent approach allowed for the preparation of sufficient amounts of psymberin (~ 0.5 g) for follow-up biological studies. Meanwhile, our highly flexible strategy enabled the design and synthesis of multiple analogs, including a psymberin-pederin hybrid, termed psympederin, that proved crucial to a comprehensive understanding of the chemical biology of psymberin and related compounds that will be described in a subsequent manuscript.

Topics: Coumarins; Crystallography, X-Ray; Models, Molecular; Molecular Structure; Pyrans; Pyrones

The potent cytotoxins pederin and psymberin have been prepared through concise synthetic routes (10 and 14 steps in the longest linear sequences, respectively) that proceed via a late-stage multicomponent approach to construct the N-acyl aminal linkages. This route allowed for the facile preparation of a number of analogs that were designed to explore the importance of the alkoxy group in the N-acyl aminal and functional groups in the two major subunits on biological activity. These analogs, including a pederin/psymberin chimera, were analyzed for their growth inhibitory effects, revealing several new potent cytotoxins and leading to postulates regarding the molecular conformational and hydrogen bonding patterns that are required for biological activity. Second generation analogs have been prepared based on the results of the initial assays and a structure-based model for the binding of these compounds to the ribosome. The growth inhibitory properties of these compounds are reported. These studies show the profound role that organic chemistry in general and specifically late-stage multicomponent reactions can play in the development of unique and potent effectors for biological responses.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Coumarins; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Molecular Conformation; Pyrans; Pyrones; Stereoisomerism; Structure-Activity Relationship

In this letter we describe an efficient synthesis of "psympederin", a hybrid between the novel antitumor natural product psymberin and the blister beetle toxin pederin. Evaluation of antiproliferative activity reveals that the dihydroisocoumarin fragment is important for psymberin toxicity and the cyclic pederate fragment is important for pederin/mycalamide toxicity. On the basis of preliminary results described herein, we speculate that, despite their structural resemblance, psymberin and pederin/mycalamide induce toxicity through different mechanisms. [reaction: see text].

Topics: Cell Line, Tumor; Cell Proliferation; Coumarins; Drug Screening Assays, Antitumor; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Pyrans; Pyrones; Sensitivity and Specificity; Structure-Activity Relationship

[reaction: see text] Psymberin is a sponge-derived natural product that shows striking selectivity as a cytotoxic agent. Conformational mobility has precluded stereochemical assignment for the acyl fragment of this molecule (psymberic acid) by NMR. Herein we report stereoselective syntheses of all four stereoisomers of psymberic acid. A comparison of the acid-mediated cyclization products of these compounds to the product of psymberin's acidic methanolysis showed the stereochemical configuration of this fragment to be 4S,5S.

Topics: Amides; Amines; Biological Products; Chromatography, Gas; Coumarins; Molecular Structure; Pyrans; Pyrones; Stereoisomerism

[structure: see text] Bioassay-guided fractionation of the sponge Psammocinia sp. afforded psymberin (1) possessing 5S,8S,9S,11R,13R,15S,16R,17R stereochemistry. Psymberin exhibits structural similarities to the pederin family metabolites. The potent cytotoxicty and unique structural features of 1 make it a promising lead for therapeutic development.

Topics: Animals; Cell Line, Tumor; Cell Survival; Coumarins; Drug Screening Assays, Antitumor; Humans; Molecular Conformation; Porifera; Pyrans; Pyrones; Stereoisomerism