Part I. The synthesis and structure-activity relationship study of azo dye related HIV replication inhibitors. Part II. Plant isolation of signalling pathways inhibitors as anti-cancer agents.

摘要

Since HIV-1 was identified as the causative agent of AIDS, many polyanionic compounds have been found possessing anti-HIV activity. Among them, several commercial dyes, such as Chicago Sky Blue, Even's Blue, Congo Red, and Direct Orange 15, attracted a lot of attention, because of their specificity and different mechanisms of actions from AZT. Quinobene, which was modeled after Chicago Sky Blue, surpassed this dye in activity. But two drawbacks prevented quinobene from further consideration in clinical evaluation: low bioavailability and highly intense color. In this part of my research, a series of compounds, structurally related to quinobene and Direct Orange 15, were prepared in an effort to improve these pharmacological properties, and to provide a structure-activity relationship (SAR). Several compounds of much lighter color showed potent activity in the NCl in vitro assay. Some interesting SARs have been observed, such as the observation that azo linkages could be replaced with other groups of similar size and configuration, such as amide, without loss of activity.; Intracellular signal transduction pathways play an important role in tumorigenesis, because two thirds of known proto-oncogenes act by coding for components of these pathways. Proteins encoded by these oncogenes, which are constitutively active analogs, under certain circumstances, lead to the cell's neoplastic transformation. Therefore, oncogene signal transduction is a logical target at which to direct a new anticancer drug development. In this research, specific components targeted included various growth factors (vasopressin, bradykinin, and platelet-derived growth factor), and enzymes (phosphoinositide specific phospholipase C, phosphatidylinositol-3-kinase, tyrosine protein kinase, and protein kinase C). A large number of plant extracts were assayed against these targets. Four plant extracts, Geranium carolinium, Polygonum pennsylvanicum, Daucus carota, and Rhododendron catawbinse, were found active. Bioassay-directed fractionation of these active extracts led to potent inhibitors. A pure compound from R. catawbinse, dendropanoxide, was identified for the first time as a PKC inhibitor. A herbicide, oryzalin, was accidentally found to be an excellent inhibitor against Ca{dollar}sp{lcub}2+{rcub}{dollar} signalling and several tumor cell lines. Several other active compounds were also isolated, but were not identified due to insufficient quantities.