Department of Pharmacology and Therapeutics
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo NY USA 14263
Tel: 716 - 845 - 2326
Fax: 716 - 845 - 8857
E-mail: brajeswar.paul@roswellpark.org

Program
Organic Synthesis; Drug Scale-up

Chemistry plays an important role(s) in the development of anticancer drugs and in the study of a number of cancer-related subjects.  The Chemistry Resource Laboratory is an institute resource and an integral part of the antitumor drug development program at Roswell Park.  This facility provides chemistry services to Roswell Park staff members in support of their efforts to develop new cancer therapies and compounds for use in studies related to cancer.  The main function of the facility is to synthesize large quantities of potential anticancer agents for detailed biological studies, including preclinical pharmacology and toxicology.  This facility has the expertise and state-of-the-art equipment to deal with all aspects of medicinal chemistry.

Progress

Potential anticancer agents that showed significant activity when tested in various in vitro cell cultures and in the preliminary in vivo system, were synthesized.  We are currently working on the following projects: I.)Dr. Sen and his coworkers have developed a liposomal system (Thermosomes) for targeted delivery of chemotherapeutic drugs to tumors, releasing their aqueous content.  Paclitaxel being hrdrophobic is not suitable for administration using Thermosomes.  The linking of the positively charged multimeric peptide (example: 5-10 mer polyarginine) is designed to make Paclitaxel soluble in buffer and facilitate its encapsulation in Thermosome.  Paclitaxel is converted to 2’ hemisuccinyl derivative which on condensation with arginine hexamer is expected to give the desired product.  II.) 17b-Hydroxy-steriod Dehydrogenase 1 (17b-HSD 1) is a key enzyme for the reduction of estrone to the most potent estrogen, 17b-estradiol in breast tissues.  Dr. Ghosh has determined the three dimensional structure of the enzyme and its complexes with some of the lead compounds.  The long term goal is to rationally design and the synthesis of inhibitors to target the enzyme for lowering estradiol level in the breast as a mode of prevention and treatment of hormonal breast cancer.  Based on the computational chemistry and molecular modeling, several estrone derivatives modified at position 2,9,16,17 have been designed.  As an initial step, substitution at position 2 of the aromatic ring A by 2-aminoethyl and 2-hydroxyethyl groups were selected and synthesized starting from estrone.  The synthesis involves 6-9 steps.  III.) Dr. Box and his coworkers have identified Deoxyribosyl formylamine (dF) as a major oxidative DNA damage lesion product, and is a degradation product of thymidine.  2-Deoxy-5-0-(4,4’-dimethoxytrityl-b-D-ribofuranosyl-1-formamide is intermediate for the synthesis of dinucleotide and oligonucleotides containing the formamide (dF) lesion.  Starting with thymidine, the synthesis of the desired intermediate involves 5 steps.  The current study is to determine the ways in which the formamide lesion affects normal Watson-Crick base pairing and how various DNA sequences containing the lesion may promote mutations (carcinogenesis). 

Select Publication

Stokes DM, Paul B, Alderfer JL, Wollman RM, Srikrishnan T.  Synthesis, structure, and conformation of anti-tumor agents in the solid and solutions states:  Hydroxyl derivatives of Ftorafur.  Nucleosides Nucleotides Nucleic Acids, 21 (11-12):863-882, 2002.