Sarawak Medichem Pharmaceuticals, Inc.

University of Illinois

Nanosphere, Inc.

Advanced Life Sciences, Inc.

Medichem Research, Inc.

Synchem, Inc.

Ze-Qi Xu

Michael T Flavin

Albert Khilevich

John D Rizzo

Lin Lin

Vilayphone Vilaychack

David Zembower

Shuyuan Liao

Sergey Dzekhster

Darko Brankovic

Jinjun Liu

Aye Mar

Abram Kivovich Sheinkman

Wei Chen

Jerome W Kosmeder, Ii

John M Pezzuto

Nian E Zhou

Alla Kucherenko

William A Boulanger

Jennifer Crabb

Hongwei Yuan

Miriam Elaine Goldsmith

Hua Cao

Ailing Li

Raghu Samy

Yasheen Zhou

Yuh-Meei Lin

Qianli Wang

Zhiqiang Fang

Livia A Enache

Vilayphone Vilaychak

Yuh Meei Lin

Tuah R Jenta

Herbert M Anderson

Augustine Rudolph Joseph

Michael J Williams

Krzysztof Pupek

The present invention relates to linker molecules that readily conjugate cellular recognition ligand at one end and drug payload at the other, and are useful in treating or preventing cancer, an autoimmune disease, an inflammatory condition, a central nervous system disorder or an infection. The linker inker molecules of the invention are represented by Formula I, II and III; Linker-Drug compounds represented by Formula IV, V and VI; and Ligand-Linker-Drug conjugates represented by Formula VII, VIII and IX: 

Thiol-ene click chemistry for drug conjugates

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

A composition and method of preventing or inhibiting tumor growth and, more particularly, of treating a malignant tumor, using prodrugs of plant-derived compounds and derivatives is disclosed. In the method, a composition containing betulinic acid or a betulinic acid derivative is administered in a prodrug form to release betulinic acid or a betulinic acid derivative in vivo at the tumor site.

Method of preparing and use of prodrugs of betulinic acid derivatives

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

The present invention relates to methods for preparing 2,2-dimethyl-5-acyloxy -10-propyl-2H,8H-benzo&lsqb;1,2-b:3,4-b&prime;&rsqb;dipyran-8-one (5) and 2,2-dimethyl-5-hydroxy-10 -propyl-2H,8H-benzo&lsqb;1,2-b:3,4-b&prime;&rsqb;dipyran-8-one (6) and their use as intermediates for the synthesis of antiviral calanolide compounds. For example, Fries rearrangement on compound 5 or Friedel-Crafts reaction on 6, yields intermediate 2,2-dimethyl-5-hydroxy -6-propionyl-10-propyl-2H,8H-benzo&lsqb;1,2-b:3,4-b&prime;&rsqb;dipyran-8-one (4), which, in turn, can be converted to (&plus;)-calanolide A and (&minus;)-calanolide B. The coupling of compound 6 with the appropriate chiral molecule under Mitsunobu or nucleophilic displacement leads to the asymmetric synthesis of antiviral calanolide compounds.

Methods for preparing antiviral calanolide compounds

The present invention relates to methods for preparing 2,2-dimethyl-5-acyloxy-10-propyl-2H,8H-benzo&lsqb;1,2-b:3,4-b&prime;&rsqb;dipyran-8-one (5) and 2,2-dimethyl-5-hydroxy-10-propyl-2H,8H-benzo&lsqb;1,2-b:3,4-b&prime;&rsqb;dipyran-8-one (6) and their use as intermediates for the synthesis of antiviral calanolide compounds. For example, Fries rearrangement on compound 5 or Friedel-Crafts reaction on 6, yields intermediate 2,2-dimethyl-5-hydroxy-6-propionyl-10-propyl-2H,8H-benzo&lsqb;1,2-b:3,4-b&prime;&rsqb;dipyran-8-one (4), which, in turn, can be converted to (&plus;)-calanolide A and (&minus;)-calanolide B. The coupling of compound 6 with the appropriate chiral molecule under Mitsunobu or nucleophilic displacement leads to the asymmetric synthesis of antiviral calanolide compounds.

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

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

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.

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Naperville, IL, United States of America

Ze-Qi Xu