Diphenyl quinolines and isoquinolines: synthesis and primary biological evaluation.
The synthesis of a series of 35 substituted 3,4-diphenyl quinolines and isoquinolines is described. The majority of these molecules differ from all other triphenylethylene based antiestrogens by a different spatial location of the aminoalkyl side chain. The binding affinity of the most representative molecules (8, 9, 19, 20, 21, 23 and 25), including analogues 8 and 21 without the side chain, for the estrogen receptor alpha (ER) was determined. The ability of these molecules to induce the progesterone receptor was also studied. Antiproliferative activity was evaluated on MCF-7 human breast cancer cells, while intrinsic cytotoxic/cytostatic properties resulting from interaction with other targets than ER were assayed on L1210 murine leukemia cells. Introduction of an aminoalkylamino side chain at carbon 2 confers strong cytotoxic properties to diphenylquinolines 9 and 10 as well as pure antiestrogenic activities. However, cytotoxicity is so high with respect to antiestrogenicity that the latter was clearly observable only in one case (9b). The structure of compound 9b was determined by X-ray crystallography. Molecular modeling of its docking within the hormone-binding domain of the receptor was subsequently undertaken. According to our results, the design of molecules with the side chain bound to the ethylene part of the triphenyl ethylene skeleton might generate compounds of potential pharmacological interest.
Croisy-Delcey
M
M
UAMR 176 CNRS lnstitut Curie-Recherche, Laboratoire Raymond Latarjet, Centre Universitaire, Orsay, France. martine.croisy@curie.u-psud.fr
Croisy
A
A
Carrez
D
D
Huel
C
C
Chiaroni
A
A
Ducrot
P
P
Bisagni
E
E
Jin
L
L
Leclercq
G
G
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020847:Estrogen Receptor Modulators; D007546:Isoquinolines; D011804:Quinolines; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone