Phytochemical study of Psoralea glandulosa, Cestrum parqui and Indigofera heterantha ; Rearrangement mechanism in oxidation of Thiophene aminotriazinone ; Synthesis of amino acid and peptide analogues of chicoric acid as HIV-1 integrase inhibitors

Abstract

Natural products have played and continue to play an invaluable role in the drug discovery process related to all disease types. One advantage of medicinal plants is that some screening has already been done by a long history of usage by traditional healers of indigenous cultures. Therefore, there is a much better chance to find drug leads. Three plants, Psoralea glandulosa , Cestrum parqui and Indigofera heterantha were studied for anti-feedant activity, dopaminergic activity and antitumor activity, respectively. Bioassay guided isolation gave ten compounds including bakuchiol analogs, an isoflavone, furanocoumarins from Psoralea glandulosa , chlorogenic acid from Cestrum parqui and berberine and 8-oxyberberine from Indigofera heterantha . The acquired immunodeficiency syndrome (AIDS) pandemic has promoted an intensive effort to identify and synthesize new drugs to target its causative agent, the human immunodeficiency virus (HIV). Preliminary studies in this laboratory examined 60 Kallawayan plants for anti-HIV activity which ultimately led to a new class of HIV type 1 integrase inhibitors. The lead compound in this series, L-dicaffeoyltartaric acid or L-chicoric acid. Structure-activity relationship studies (SAR) found that at least one carboxylic acid and two catechols are necessary. Different linkages between the two catechols and the carboxylic groups can change the anti-HIV IN activities. Analogs with two amide linkages, one amide and one ester linkage, two amine linkages, peptide linkages and heterocyclic linkages have been synthesized. Replacement of the ester by an amide linkage retains but modifies the anti-HIV IN activity. The amine linkage resulted in the loss of activity. Analogs with peptide and heterocyclic linkages have only moderate activity. Modification of the catechols to galloyl groups gave active N ? , N ? -bis-galloyl-2,3-diaminopropionic acid, highly toxic digalloyltartaric acid and inactive N ? , N &egr; -bisgalloyllysine. Oxidation of thiophene aminotriazinone in methanol gave 99.3% 5a and 0.7% rearrangement product 5 . The rearrangement mechanism was investigated with a 13 C labeled precursor. Two possible mechanisms were suggested (Scheme 1). Either the 13 C will be scrambled if the intermediate is the cumulated ketene 22 but remain at C-2 if the cyclopropanone mechanism is operative. The latter result was found.* *Please refer to dissertation for diagrams.