Harvard College

Jakub Svenda

Andrew G Myers

Daniel Jonathan Smaltz

Nicholas E Hill

Robert T Yu

Thomas Magauer

Seth Herzon

Jeremy Earle Wulff

Romain Siegrist

Matthew Allen Zajac

Thomas Maguer

The present invention relates to trioxacarcin compounds of the formula: or pharmaceutically acceptable forms thereof; wherein R, R, R, R, R, R, R, R, and Rare as defined herein. The present invention also provides processes for preparing such compounds and intermediates thereto; pharmaceutical compositions comprising such compounds; and methods of use and treatment.

Trioxacarcins and uses thereof

The present invention relates to trioxacarcin compounds of the formula: (I) or pharmaceutically acceptable forms thereof; wherein R, R, R, R, R, R, R, R, and Rare as defined herein. The present invention also provides processes for preparing such compounds and intermediates thereto; pharmaceutical compositions comprising such compounds; and methods of use and treatment. 

The syntheses of the natural products, avrainvillamide and stephacidin B, are provided. The &#x3b1;,&#x3b2;-unsaturated nitrone functionality of avrainvillamide and its 3-alkylidene-3H-indole 1-oxide core is shown to covalently and reversibly bond to heteroatom-based nucleophiles. This capability may allow these molecules to bind active site nucleophiles and may provide the basis for designing potent and selective enzyme inhibitors. Both avrainvillamide and its dimer stephacidin B have been reported to exhibit antiproliferative activity, and avrainvillamide has been reported to exhibit antimicrobial activity against multi-drug resistant bacteria. Avrainvillamide has been found to target cytoskeleton-linking membrane protein (CLIMP-63) thereby preventing cells from undergoing mitosis. The invention provides syntheses of these natural products as well as analogs of these natural products and their functional cores. The compounds of the invention may be used in the treatment of diseases such as cancer, autoimmune diseases, and bacterial infection.

Synthesis of avrainvillamide, strephacidin B, and analogues thereof

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Cambridge, MA, United States of America

Jakub Svenda