Exploitable results
A novel prodrug approach has been developed to deliver directly the 5'-monophosphate derivative of purine and pyrimidine nucleoside analogues (i.e. AZT, d4T, ddA, d4A, etc.) into intact cells. These prodrugs display a pronounced activity against HIV and/or HBV, and in a number of cases, they proved by far superior in antiviral potency and selectivity than the parent compounds.
Convenient and efficient synthesis methods for modified nucleoside triphosphonates and dinucleoside 5',5'-O-tetra-phosphates have been developed, and investigated as substrates for HIV reverse transcriptase and human DNA polymerases alpha, beta and epsilon. The chain-terminating properties of the phosphonates were examined. Although a modestly decreased substrate activity was noticed for several of the compounds, a markedly greater (serum and cell culture) stability was found. Interesting antiviral activities were observed.
Studies on the phosphonate isosteres of nucleoside 3'- and 2'-phosphates as precursors of the related oligonucleotides were performed. Successful routes for preparation of isosteric phosphonates could be accomplished.
Design and synthesis of various new modified nucleosides (including substituted uracil, thymine and cytosine as the base part) was performed, and the physical and chemical properties investigated. Antiviral and anticancer evaluation revealed several potential leads that are currently under further investigation. Also, new transformation products of 3-hydroxymethylindole, ascorbigen and 3-formylindole have been obtained with strong cytostatic properties.
In the antitumor field, an original series of 6-fluoroquinolones, bearing new substituents at C-7 of the quinolone ring, fluorinated polycyclic compounds, pentacyclic fluoroquinolones and triazolo [1,5-a] pyrimidines were synthesized and evaluated for their cytostatic activity against a panel of tumor cell lines, including leukemia, colon cancer, CNS cancer, melanoma, ovary, prostate, renal and breast cancer. Particularly among the polycyclic fluoroquinolones, new cytostatic agents were discovered with potential antitumor activity.
More than 100 new anthracycline derivatives have been synthesized. The 14-hydroxy derivatives showed the most interesting cytostatic activities. Several 14-hemiesters and 14-hydroxycarminomycin were found to be able to overcome resistance to adriamycin in experimental tumor systems in cell culture.
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