The Texas A&M University System

Johns Hopkins University

Burnham Institute for Medical Research

Sanford-burnham Medical Research Institute

Universidade De Santiago De Compostela

Daniel Romo

Jeffrey W Smith

Jun O Liu

Omar Robles

Vikram C Purohit

Gil Ma

Nam Song Choi

Zonggao Shi

Mingzhao Zhu

Steven J Kridel

Fumiko Axelrod

Tilman Schneider-Poetsch

Ken Hull

Yongjun Dang

Woon-Kai Low

Robyn Richardson

Maria Amparo Alfonso Rancano

Manuel Zancanella

Sung Wook Cho

Huda Henry-Riyad

Mikail E Abbasov

Miguel Luis Botana Lopez

Changsuk Lee

Henry Nguyen

Seongho Oh

Kenneth G Hull

Eva Alonso Lopez

Kenneth Hull

Jong Gao Shi

Gracilin A congeners and methods for their use as immunosuppressive and neuroprotective agents.

Gracilin A and congeners as immunosuppressive and neuroprotective agents

Pateamine A derivatives, pharmaceutical compositions that include the derivatives, and methods for treating chronic lymphocytic leukemia using the derivatives.

Beta-amino pateamine a derivatives and methods for treating chronic lymphocytic leukemia

Pateamine A derivatives and pharmaceutical compositions that include the derivatives. The pateamine A derivatives are &#x3b1;-amino pateamine A derivatives that lack the C5-methyl group of pateamine A.

Alpha-amino pateamine A derivatives and methods for treating chronic lymphocytic leukemia

Provided herein include compositions, all related stereoisomers as well as pharmaceutically acceptable salts provided as simplified analogs of pateamine A, in which the analogs generally are devoid of the C3-amino and C5-methyl groups, also referred to as desmethyl, desamino-pateamine A. Suitable analogs provide anticancer and antiproliferative effects in vivo and in vitro by a novel drugs mechanism of action described herein for pateamine A, including inhibition of eIF4A-dependent translation initiation. As with pateamine A, as described herein, suitable analogs cause cell cycle arrest or induce apoptosis in transformed cells. However, toxicity of such compounds to slow growing normal cells is low. In addition, such analogs, like pateamine A, target translation initiation factors and are useful as anticancer and antiproliferative agents in subjects in need thereof. Moreover, the analogs, like pateamine A, are valuable molecular probes for evaluation of eukaryotic translation initiation and as lead compounds for development of improved anticancer agents.

Potent immunosuppressive agents, derivatives and uses

The present invention provides compounds having the general structure A, or a pharmaceutically acceptable derivatives thereof: wherein R is an alkyl group, and Rcomprises at least one moiety selected from a group consisting of an alkyl, an alkenyl, an aryl, a heterocycle, hydroxyl, ester, amido, aldehyde, and a halogen.

Beta-lactone compounds

The present invention features methods of treating a cancer in a subject by administering an effective amount of a beta-lactone to the subject. The invention also features methods of inhibiting angiogenesis in a subject by administering an effective amount of an inhibitor of fatty acid synthase to the subject. These methods can be used to treat a variety of cancers and other diseases and conditions. The invention also features methods of identifying beta-lactones and other compounds that can be used in the methods of the invention for the treatment of tumors, inhibition of angiogenesis, and the treatment of diseases and conditions that involve pathological angiogenesis. The invention also features methods of synthesizing beta-lactones and features novel beta-lactone compounds.

Method for the asymmetric synthesis of beta-lactone compounds

Derivatives of belactosin and their synthesis are disclosed. In certain embodiments, compounds of the present invention exhibit anti-cancer, antiviral, antibiotic, and/or auto-immune therapeutic abilities. In general, methods of synthesis disclosed herein allow for introduction of a variety of substituents at numerous positions as well as the facile introduction of a beta-lactone ring moiety. The synthetic steps comprise, in preferred embodiments, a tandem Mukaiyama aldol lactonization reaction. Data demonstrating the utility of some of the derivatives as proteasome inhibitors is also disclosed.

Belactosin derivatives as therapeutic agents/biological probes and their synthesis

The present invention provides a concise synthetic method for generating lactam-fused beta-lactones that feature, in some embodiments, a tertiary fused carbinol, quaternary carbons, and a reactive beta-lactone moiety available for further reactions. The present invention further provides compounds synthesized by this method as well as methods of using these compounds as inhibitors of the proteasome and fatty acid synthase.

Cyclic-fused beta-lactones and their synthesis

Provided herein are compositions, all related stereoisomers as well as pharmaceutically acceptable salts provided as simplified analogs of pateamine A, in which the analogs generally are devoid of the C3-amino and C5-methyl groups, also referred to as desmethyl, desamino-pateamine A. Suitable analogs provide anticancer and antiproliferative effects in vivo and in vitro by a novel drug mechanism of action described herein for pateamine A, including inhibition of eIF4A-dependent translation initiation. As with pateamine A, as described herein, suitable analogs cause cell cycle arrest or induce apoptosis in transformed cells. However, toxicity of such compounds to slow growing normal cells is low. In addition, such analogs, like pateamine A, target translation initiation factors and are useful as anticancer and antiproliferative agents in subjects in need thereof. Moreover, the analogs, like pateamine A, are valuable molecular probes for evaluation of eukaryotic translation initiation and as lead compounds for development of improved anticancer agents.

Anticancer agents and use

The present invention provides a compound of Formula I, all of its related stereoisomers, and their pharmaceutically acceptable salts, wherein A&#x2014;B, K, Q, X, Y, Z, R and R1 are as defined in Claim. The present invention also provides processes for the preparation thereof, the use thereof in treating immune mediated disease and conditions, and pharmaceutical compositions for use in such therapy 

Potent, simplified derivatives of pateamine A

Growing community of inventors

College Station, TX, United States of America

Daniel Romo