STUDY OF THE EFFECTS OF BASIC DI-PHENYL AND TRI-PHENYL DERIVATIVES ONMALIGNANT-CELL PROLIFERATION - AN EXAMPLE OF THE APPLICATION OF CORRESPONDENCE FACTOR-ANALYSIS TO STRUCTURE-ACTIVITY-RELATIONSHIPS (SAR)

The descriptive multivariate method known as Correspondence Factor Ana lysis (CFA) was used to establish correlations between the structures of three chemical classes of compounds (triphenylacrylonitriles (TPEs) , diphenylethylenes (DPEs), and diphenylalkyls) substituted in the par a position by either hydroxy or basic groups and their responses in a battery of three biochemical tests, namely the induction of the prolif eration of the MCF- human breast cancer cell-line, the estrogen-irreve rsible inhibition of MCS cell proliferation (herein denoted cytotoxici ty), and binding to the estrogen receptor (ER). The power of CFA was i llustrated by performing several analyses: (a) Construction of factori al maps that described only the specificity of the response of the TPE population in the tests or both the specificity and amplitude of the response; (b) Use of the factorial maps as mathematical models for the introduction of new variables. These variables were either further bi ochemical tests (cytotoxicity under different conditions, inhibition o f the activation of protein kinase C) on which the TPE population had been screened or further compounds (DPEs and diphenylalkyls). Relation ships among the different tests were thus assessed as well as affiliat ions of the new compounds with TPEs. The analyses revealed the importa nce of the presence and configuration of hydroxy groups in ER binding and cell proliferation, but also the ability of non-hydroxylated compo unds to induce cell growth independently of their relative affinity fo r ER. Cytotoxicity could be related to the presence of basic groups bu t also to resonance of conjugated bis-para-hydroxy diphenyl derivative s. Overall, the analyses stressed the complexity of the relationships between growth-promoting and growth-inhibitory potential of the test-c ompound populations and suggested the involvement of multiple mechanis ms of action.