Research Triangle Institute

Other

US Government as Represented by the Secretary of the Army

Govindarajan Manikumar

Mansukh C Wani

Monroe E Wall

Allan W Nicholas

Dolatrai M Vyas

Neelakantan Balasubramanian

Michael A Wall

Yves Pommier

Babu J Mavunkel

David J Adams

Hikmat A Musallam

Michael P Gamcsik

Atanu Biswas

O Michael Colvin

Srinivasan Varadarajan

Daniel J Dahlhausen

Richard J Sundberg

Camptothecin analogs having an E-ring ketone are effective anti tumor compounds. These compounds inhibit the enzyme topoisomerase I and may alkylate DNA of the associated topoisomerase I DNA cleavable complex.

Camptothecin analogs having an E-ring ketone

Methods of forming camptothecin compounds which are effective anti-tumor compounds are disclosed. These compounds inhibit the enzyme topoisomerase I and may alkylate DNA of the associated topoisomerase I-DNA cleavable complex.

7-substituted camptothecin and camptothecin analogs and methods for producing the same

Camptothecin compounds which are effective anti-tumor compounds are disclosed. These conjugates inhibit the enzyme topoisomerase I and enhance the stability of the topoisomerase I-DNA cleavable complex.

Camptothecin compounds with a thioether group

&bgr;-Alanine esters of camptothecin compounds which are effective anti-tumor compounds are disclosed. These compounds inhibit the enzyme topoisomerase I and may alkylate DNA of the associated topoisomerase I-DNA cleavable complex.

Camptothecin &bgr;-alanine esters with topoisomerase I inhibition

Camptothecin compounds having a C,O&mdash;(CF,),O group where n is 1 or 2 are effective anti-tumor compounds. These compounds inhibit the enzyme topoisomerase I and may alkylate DNA of the associated topoisomerase I-DNA cleavable complex.

10, 11-difluoromethylenedioxycamptothecin compounds with topoisomerase I inhibition

A method for synthesizing camptothecin and camptothecin analogs using a novel hydroxyl-containing tricyclic intermediate and the camptothecin analogs produced by the process. The camptothecin analogs are effective inhibitors of topoisomerase. I and show antileukemic and anti-tumor activity.

Alkyl camptothecin compounds as potent inhibitors of human colorectal

A method for synthesizing camptothecin and camptothecin analogs using a novel hydroxyl-containing tricyclic intermediate and the camptothecin analogs produced by the process. The camptothecin analogs are effective inhibitors of topoisomerase.I and show antileukemic and anti-tumor activity.

Camptothecin analogs as potent inhibitors of topoisomerase I

A camptothecin analog having the structure shown below: ##STR1## where Z is H or C.sub.1-8 alkyl and R is NO.sub.2, NH.sub.2, N.sub.3, hydrogen, halogen, COOH, OH, O-C.sub.1-3 alkyl, SH, S-C.sub.1-3 alkyl, CN, CH.sub.2 NH.sub.2, NH-C.sub.1-3 alkyl, CH.sub.2 -NH-C.sub.1-3 alkyl, N(C.sub.1-3 alkyl).sub.2, CH.sub.2 N(C.sub.1-3 alkyl).sub.2, O-, NH- or S-CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2 OH).sub.2, O-, NH- or S- CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2 OH).sub.2, O-, NH- or S-CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2 CH.sub.2 OH).sub.2, O-, NH- or S-CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2 OH.sub.2).sub.2, O-, NH- or S-CH.sub.2 CH.sub.2 N(C.sub.1-3 alkyl).sub.2, O-, NH- or S-CH.sub.2 CH.sub.2 CH.sub.2 N(C.sub.1-3 alkyl).sub.2, CHO, C.sub.1-3 alkyl or NHCOCHR.sup.1 NR.sup.2 R.sup.3, where R.sup.1 is the side-chain of an .alpha.-amino acid and R.sup.2 and R.sup.3, independently are hydrogen or a lower alkyl group or R.sup.3 is a peptide unit containing 1-3 amino acid units bonded to the nitrogen through a peptide bond; NHCO-C.sub.2-8 -alkylene-X or NHCO-C.sub.2-8 -alkenylene-X, where X is COOH; CONR.sup.2 -(CH.sub.2).sub.n -NR.sup.2 R.sup.3, where n=1-10 and R.sup.2 and R.sup.3 are as defined above; NHCO-B-(CH.sub.2).sub.n-NR.sup.2 R.sup.3, where B=oxygen or NH, or ##STR2## where m+y=3-6, and salts thereof. The campothecin compounds inhibit the enzyme topisomerase I and are useful in treating tumors and leukemia.

Method of treating tumors with anti-tumor effective camptothecin

A method for synthesizing camptothecin analogs using a novel hydroxyl-containing tricyclic intermediate and the camptothecin analogs produced by the process. The camptothecin analogs are effective inhibitors of topoisomerase.

A method for synthesizing camptothecin and camptothecin analogs using a novel hydroxyl-containing tricyclic intermediate and the camptothecin analogs produced by the process. The camptothecin analogs are effective inhibitors of topoisomerase I and show antileukemic and anti-tumor activity.

Pharmaceutical compositions and methods employing camptothecins

Novel compounds are provided which exhibit high levels of anti-parasitic activity, specifically against parasites of the genus Trypanosoma. The compounds are comprised of aryl-substituted quaternary heteroaromatic salts which include a positively charged imidazolium or other heterocyclic ring, a linking group, a phenyl ring, and a polar functional group. The polar functional group is preferably a quanylhydrazone or a heterocyclic hydrazone. A method is also provided for treating the diseases associated with Trypanosoma parasites which comprises administering to infected animals or humans an effective amount of a compound of the present invention.

Compounds exhibiting anti-parasitic activity and a method for their use

A camptothecin analog having the structure shown below: ##STR1## where Z is H or C.sub.1-8 alkyl and R is NO.sub.2, NH.sub.2, N.sub.3, hydrogen, halogen, COOH, OH, O--C.sub.1-3 alkyl, SH, S--C.sub.1-3 alkyl, CN, CH.sub.2 NH.sub.2, NH--C.sub.1-3 alkyl, CH.sub.2 --NH--C.sub.1-3 alkyl, N(C.sub.1-3 alkyl).sub.2, CH.sub.2 N(C.sub.1-3 alkyl).sub.2, O--, NH--, or S--CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2 OH).sub.2, O--, NH-- or S-- CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2 OH).sub.2, O--, NH-- or S--CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2 CH.sub.2 OH).sub.2, O--, NH-- or S--CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2 CH.sub.2 OH.sub.2).sub.2, O--, NH-- or S--CH.sub.2 CH.sub.2 N(C.sub.1-3 alkyl).sub.2, O--, NH-- or S--CH.sub.2 CH.sub.2 CH.sub.2 N(C.sub.1-3 alkyl).sub.2, CHO, C.sub.1-3 alkyl or NHCOCHR.sup.1 NR.sup.2 R.sup.3, where R.sup.1 is the side-chain of an .alpha.-amino acid and R.sup.2 and R.sup.3, independently are hydrogen or a lower alkyl group or R.sup.3 is a peptide unit containing 1-3 amino acid units bonded to the nitrogen through a peptide bond; NHCO--C.sub.2-8 -alkylene--X or NHCO--C.sub.2-8 -alkenylene--X, where X is COOH; CONR.sup.2 --(CH.sub.2).sub.n --NR.sup.2 R.sup.3, where n=1-10 and R.sup.2 and R.sup.3 are as defined above; NHCO--B--(CH.sub.2).sub.n --NR.sup.2 R.sup.3, where B=oxygen or NH, or ##STR2## where m+y=3-6, and salts thereof.

10,11-methylenedioxy-20(RS)-camptothecin and

A method for synthesizing camptothecin and camptothecin analogs using a novel hydroxyl-containing tricyclic intermediate and the camptothecin analogs produced by the process. The camptothecin analogs are effective inhibitors of topoisomerase I and show anti-leukemic and anit-tumor activity.

Camptothecin and analogs thereof and pharmaceutical compositions and

A camptothecin analog having the structure shown below: ##STR1## wherein R is NO.sub.2, NH.sub.2, NHCOCHR.sup.1 NR.sup.2 R.sup.3, where R.sup.1 is the side-chain of an .alpha.-amino acid and R.sup.2 and R.sup.3, independently are hydrogen or a lower alkyl group or R.sup.3 is a peptide unit containing 1-3 amino acid units bonded to the nitrogen through a peptide bond, NHCO--C.sub.2-8 -alkylene-X or NHCO--C.sub.2-8 -alkenylene-X, where X is COOH or CONR.sup.2 --(CH.sub.2).sub.n --NR.sup.2 R.sup.3, n=1-10 and R.sup.2 and R.sup.3 are as defined above, NHCO--Z--(CH.sub.2).sub.n --NR.sup.2 R.sup.3, where z=oxygen or NH, or ##STR2## where m+y=3-6 and salts thereof.

10,11-methylenedioxy-20(RS)-camptothecin analogs

A method for synthesizing camptothecin and camptothecin analogs using a novel hydroxyl-containing tricyclic intermediate and the camptothecin analogs produced by the process. The camptothecin analogs are effective inhibitors of topoisomerase I and show anti-leukemic and anti-tumor activity.

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Raleigh, NC, United States of America

Govindarajan Manikumar