Sarawak Medichem Pharmaceuticals, Inc.

Medichem Research, Inc.

Advanced Life Sciences, Inc.

Nanosphere, Inc.

Michael T Flavin

Ze-Qi Xu

John D Rizzo

Albert Khilevich

Lin Lin

Vilayphone Vilaychack

David Zembower

Yuh-Meei Lin

David E Zembower

Darko Brankovic

Sergey Dzekhster

Shuyuan Liao

Aye Mar

Jinjun Liu

Alla Kucherenko

Abram Kivovich Sheinkman

William A Boulanger

Wei Chen

Lisa M Seaney

Ralph Schure

Gen-Xian Zhao

Yasheen Zhou

Deanna J Nelson

Ralph M Schure

Livia A Enache

Yuh Meei Lin

Vilayphone Vilaychak

Heping Zhang

Gary Jesmok

Julian F Borgia, Deceased

Krzysztof Pupek

Tuah R Jenta

Abram K Sheynkman

Herbert M Anderson

Yibo Xu

Geng-Xian Zhao

Michael J Williams

The present invention relates to anti-tumor compounds, compositions and methods. In particular, the invention relates to indolocarbazole analogues of the following general formulas that inhibit topoisomerase I activity 

Indolocarbazole anticancer agents and methods of using same

The present invention relates to compounds and compositions useful in treating or preventing conditions and diseases related to Mycobacterium infection, and methods of use directed thereto.

Pyranocoumarin compounds as a novel pharmacophore with anti-TB activity

Substantially purified antiviral biflavanoids robustaflavone, hinokiflavone, amentoflavone, agathisflavone, volkensiflavone, morelloflavone, rhusflavanone, succedaneaflavanone, GB-1a, and GB-2a are provided. Antiviral biflavanoid derivatives and salt forms thereof, e.g., robustaflavone tetrasulfate potassium salt, and methods for preparing the same are also disclosed. Pharmaceutical compositions which include the antiviral biflavanoids, derivatives or salts thereof are also provided alone or in combination with at least one antiviral agent such as 3TC. Also disclosed is an improved method for obtaining substantially pure robustaflavone from plant material. The biflavanoid compounds, derivatives or salts thereof of the invention may be used in a method for treating and/or preventing viral infections caused by viral agents such as influenza, e.g., influenza A and B; hepatitis, e.g., hepatitis B; human immunodeficiency virus, e.g., HIV-1; Herpes viruses (HSV-1 and HSV-2); Varicella Zoster virus (VZV); and measles. For instance, semi-synthetic hexa-O-acetate and hexa-O-methyl ether derivatives of robustaflavone have been found to be effective in a method for treating or preventing hepatitis B viral infections. Compositions which include these robustaflavone derivatives along with methods for preparing and using the same are also provided. These compositions may be used alone or in combination with at least one antiviral agent such as 3TC.

Biflavanoids and derivatives thereof as antiviral agents

Calanolide analogues that demonstrate potent antiviral activity against many viruses are provided. Also provided is a method of using calanolide analogues for treating or preventing viral infections. The calanolide analogues provided are obtained via syntheses employing chromene 4 and chromanone 7 as key intermediates.

Calanolide analogues and methods of their use

Calanolides and analogues thereof that demonstrate potent mycobacterium activity are provided. Also provided is a method of using calanolides and analogues thereof for treating or preventing mycobacterium infections. The calanolides and analogues thereof provided are obtained via syntheses employing chromene 4 and chromanone 7 as key intermediates.

Method for treating and preventing mycobacterium infections

Robustaflavone, intermediates and analogues thereof and a method for synthesizing the same are provided. The method involves constructing apigenin ethers containing functionalities at the 6- and 3&prime;-positions which could be cross-coupled using transition metal catalysis. The method also involves development of a regioselective iodination of an apigenin derivative at the 6-position, formation of an apigenin 3&prime;-boronate using a palladium-catalyzed exchange of the corresponding 3&prime;-iodide with a diboron reagent. Finally, Suzuki coupling to form the sterically congested 6-3&prime;&Prime; biaryl bond of robustaflavone provides access to the desired biflavanoid system. Robustaflavone intermediates and analogues may be used to prepare analogues of other biflavanoids such as hinokifavone, rhusflavone and succedaneaflavone.

Robustaflavone, intermediates and analogues and method for preparation thereof

A method and workstation for optimizing chemical processes based on combinatorial chemistry, automation technology, and computer-controlled design is disclosed. The workstation includes a synthesizer, an analyzer, a robot and computer in communication with the synthesizer and analyzer. The computer includes one or more programs for regulating reaction parameters such as temperature, pressure, concentration of reagents and employs statistical methods for optimizing multiple reaction parameters and for designing optimized experiments for further investigation.

Use of automated technology in chemical process research and development

An efficient and scalable method is reported for the isolation of costatolide (2), an HIV-1-specific nonnucleoside reverse transcriptase inhibitor (NNRTI), from the latex of Calophyllum plants such as C. teysmannii var. inophylloide. An overall yield of 10.6% of costatolide, with a purity of 96%, was obtained by repetitive recrystallization of the latex from a single organic solvent after the oily material was removed by treatment with hexane. A second major component of the latex, soulattrolide (3), another HIV-1 NNRTI, was also isolated. Both compounds were characterized by spectroscopic and chromatographic analyses and their in vitro anti-HIV activities were also confirmed. The results suggest that sufficient supplies of costatolide can be obtained in a relatively low-cost manner from natural sources.

Scalable method for the isolation of anti-HIV agents from the tropical

A method of preparing (.+-.)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. Useful intermediates for preparing (.+-.)-calanolide A and its derivatives are also provided. According to the disclosed method, chromene 4 intermediate was reacted with acetaldehyde diethyl acetal or paraldehyde in the presence of an acid catalyst with heating, or a two-step reaction including an aldol reaction with acetaldehyde and cyclization either under acidic conditions or neutral Mitsunobu conditions, to produce chromanone 7. Reduction of chromanone 7 with sodium borohydride, in the presence of cerium trichloride, produced (.+-.)-calanolide A. A method for resolving (.+-.)-calanolide A into its optically active forms by a chiral HPLC system or by enzymatic acylation and hydrolysis is also disclosed. Finally, a method for treating or preventing a viral infections using (.+-.)-calanolide or (-)-calanolide is provided.

Method for the preparation of (.+-.)-calanolide A and intermediates

A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (.+-.)-8a. Separation and enzyme-mediated resolution of (.+-.)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.

Method for the preparation of (+)-calanolide A and analogues thereof

Substantially purified antiviral biflavanoids robustaflavone, hinokiflavone, amentoflavone, agathisflavone, volkensiflavone, morelloflavone, rhusflavanone, succedaneaflavanone, GB-1a, and GB-2a are provided. Antiviral biflavanoid derivatives and salt forms thereof, e.g., robustaflavone tetrasulfate potassium salt, and methods for preparing the same are also disclosed. Pharmaceutical compositions which include the antiviral biflavanoids, derivatives or salts thereof are also provided. Also disclosed is an improved method for obtaining substantially pure robustaflavone from plant material. The biflavanoid compounds, derivatives or salts thereof of the invention may be used in a method for treating and/or preventing viral infections caused by viral agents such as influenza, e.g., influenza A and B; hepatitis, e.g., hepatitis B; human immunodeficiency virus, e.g., HIV-1; Herpes viruses (HSV-1 and HSV-2); Varicella Zoster virus (VZV); and measles.

Method for the preparation of (+)-calanolide a and analogues thereof

A method of preparing (.+-.)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. Useful intermediates for preparing (.+-.)-calanolide A and its derivatives are also provided. According to the disclosed method, chromene 4 intermediate was reacted with acetaldehyde diethyl acetal or paraldehyde in the presence of an acid catalyst with heating, or a two-step reaction including an aldol reaction with acetaldehyde and cyclization either under acidic conditions or neutral Mitsunobu conditions, to produce chromanone 7. Reduction of chromanone 7 with sodium borohydride, in the presence of cerium trichloride, produced (.+-.)-calanolide A. A method for resolving (.+-.)-calanolide A into its optically active forms by a chiral HPLC system or by enzymatic acylation and hydrolysis is also disclosed. Finally, a method for treating or preventing viral infections using (.+-.)-calanolide A or (-)-calanolide A is provided.

Growing community of inventors

Darien, IL, United States of America

Michael T Flavin