University of Pittsburgh

University of Kentucky Research Foundation

Other

New Century Pharmaceuticals, Inc.

Thomas G Burke

Dennis Patrick Curran

Bom David

David Bom

Hubert B Josien

Ayhan S Demir

Ashok J Chavan

Joseph R Lakowicz

Yves Pommier

Daniel C Carter

Tie-Lin Wang

Henryk Malak

Ignacy Gryczynski

Danzhou Yang

Cihangir Tanyeli

A compound having the formula in racemic form, enantiomerically enriched form or enantiomerically pure form, and pharmaceutically acceptable salts thereof.

Camptothecin analogs and methods of preparation thereof

The present invention provides methods and formulations for optimizing the anti-cancer and anti-HIV activities of a camptothecin drug, including camptothecin and its related analogs including 9-aminocamptothecin and 9-nitrocamptothecin. The invention involves methodologies and formulations that limit human serum albumin-mediated reduction of the anti-cancer and anti-HIV effects of the camptothecins, and the methods and formulations provide combination therapies in which binding of the camptothecin agent to human serum albumin can be modulated by the administration of a competing agent that also binds human serum albumin. Reduced camptothecin drug binding to human serum albumin can result in elevated camptothecin free drug levels and thus improve the effectiveness of treatment regimens involving these drugs. Further agents such as methotrexate and AZT can also be used in cancer and HIV-positive patients employing camptothecin drugs.

Methods and compositions for optimizing blood and tissue stability of camptothecin and other albumin-binding therapeutic compounds

A compound having the formula in racemic form, enantiomerically enriched form or enantiomerically pure form; wherein X is a radical precursor; Ris a Calkyl group, an alkenyl group, an alkynyl group, or a benzyl group; Ris an alkyl group, &#x2014;Si(RRR) or &#x2014;(R)Si(RRR), wherein Ris an alkylene group, an alkenylene group, or an alkynylene group; and R, Rand Rare independently a Calkyl group, a Calkenyl group, a Calkynyl group, an aryl group or a &#x2014;(CH)Rgroup, wherein N is an integer within the range of 1 through 10 and Ris a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, &#x2014;SRor a nitro group; and Ris H, F or &#x2014;CH.

Intermediates in the preparation of homocamptothecin analogs

A compound has the formula in racemic form, enantiomerically enriched form or enantiomerically pure form. Ris preferably &#x2014;Si(RRR) or &#x2014;(R)Si(RRR), wherein Ris an alkylene group, an alkenylene group, or an alkynylene group; and R, Rand Rare independently a Calkyl group, a Calkenyl group, a Calkynyl group, an aryl group or a &#x2014;(CH)Rgroup, wherein N is an integer within the range of 1 through 10 and Ris a hydroxy group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, &#x2014;SRor a nitro group. Rcan be broadly substituted. Ris preferably a Calkyl group, an alkenyl group, an alkynyl group, or a benzyl group. Ris preferably H, F or &#x2014;CH. Ris Ris &#x2014;C(O)Ror H. The E-ring (the lactone ring) may be opened. A method of synthesis of compound (1) and intermediates in the synthesis thereof are provided.

Camptothecin drugs are stabilized in their antitumor active lactone form by complexation with an oligonucleotide including RNA or catalytic RNA. The oligonucleotide-camptothecin drug complex may be incorporated within a macromolecular assembly including both viral and non-viral oligonucleotide vectors. The invention allows combination gene and camptothecin drug therapy.

Oligonucleotide delivery systems for camptothecins

Camptothecin and homocamptothecin analogs and derivatives are provided incorporating alkylamine and polyalkylamine moieties.

Water-soluble derivatives of camptothecin/homocamptothecin

A compound and a method of synthesizing a compound having the following general formula (1): ##STR1## wherein R.sup.1 and R.sup.2 are independently the same or different and are hydrogen, an alkyl group, an alkenyl group, a benzyl group, an alkynyl group, an alkoxy group, an aryloxy group, an acyloxy group, --OC(O)OR.sup.d, wherein R.sup.d is an alkyl group, a carbamoyloxy group, a halogen, a hydroxy group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an acyl group, an amino group, --SR.sup.c, wherein, R.sup.c is hydrogen, an acyl group, an alkyl group, or an aryl group, or R.sup.1 and R.sup.2 together form a group of the formula --O(CH.sub.2).sub.n O-- wherein n represents the integer 1 or 2; R.sup.3 is H, F, a halogen atom, a nitro group, an amino group, a hydroxy group, or a cyano group; or R.sup.2 and R.sup.3 together form a group of the formula --O(CH.sub.2).sub.n O-- wherein n represents the integer 1 or 2; R.sup.4 is H, a trialkylsilyl group, F, a C.sub.1-3 alkyl group, a C.sub.2-3 alkenyl group, a C.sub.2-3 alkynyl group, or a C.sub.1-3 alkoxy group; R.sup.5 is a C.sub.1-10 alkyl group, an allyl group, a benzyl group or a propargyl group; and R.sup.6, R.sup.7 and R.sup.8 are independently a C.sub.1-10 alkyl group, a C.sub.2-10 alkenyl group, a C.sub.2-10 alkynyl group, an aryl group or a --(CH.sub.2).sub.N R.sup.9 group, wherein N is an integer within the range of 1 through 10 and R.sup.9 is a hydroxy group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group or a nitro group; and R.sup.11 is an alkylene group or an alkenylene group, and pharmaceutically acceptable salts thereof.

A method of measuring an analyte present in animal (e.g., human) tissue or fluids such as blood or plasma. The analyte is multi-photon excitable (e.g., two-photon excitable) at a first wavelength at which the animal tissue is substantially non-absorbing. The analyte fluoresces at a second wavelength upon being excited at the first wavelength. The animal tissue is irradiated with radiation at the first wavelength so as to excite the analyte through absorption by the analyte of two or more photons of the radiation at the first wavelength. Excitation of the analyte results in a fluorescent emission from the analyte of radiation at the second wavelength. The emission at the second wavelength is detected, and the concentration of analyte determined based on the detected emission.

Growing community of inventors

Lexington, KY, United States of America

Thomas G Burke