Synthesis, antiproliferative activity and estrogen receptor α affinity of novel estradiol-linked platinum(II) complex analogs to carboplatin and oxaliplatin. Potential vector complexes to target estrogen-dependent tissues.
In the course of efforts to develop 17β-estradiol-linked to anticancer agents targeting estrogen-dependent tissue, we identified three estradiol-linked platinum(II) complex analogs to cisplatin (E-CDDP) derivatives namely: VP-128 (1), CD-38 (2) and JMP-39 (3) that exhibit potent in vitro and in vivo (for derivative VP-128) activity along with interaction with the estrogen receptor α (ERα). In this study, we prepared and biologically evaluated two novel classes of estradiol-linked platinum(II) complex analogs to carboplatin (E-CarboP, 1a-3a) and oxaliplatin (E-OxaP, 1b-3b). E-CarboP and E-OxaP were designed and based on the estradiol-linker scaffold of E-CDDP derivatives previously identified. Consequently, we assessed the importance of the nature of platinum(II) salt on the antiproliferative activity on MCF-7 and MDA-MB-231 human mammary carcinoma cell lines together with affinity for the ERα by replacing the dichloroplatinum(II) moiety by a cyclobutane-1,1-dicarboxylateplatinum(II) or an oxalateplatinum(II) moiety. Except for compound 3b which is inactive at the concentration tested, the antiproliferative activity of all compounds on both human mammary carcinomas cell lines are in micromolar range and are more active than carboplatin and oxaliplatin alone but less active that their E-CDDP counterparts (1-3). In addition, E-CarboP derivatives 1a-3a show very low affinity for ERα whereas E-OxaPs 1b and 2b show higher affinity for ERα than their parents E-CDDPs (1-2), suggesting that the nature of the platinum(II) salt involved in the vector complexes is extremely important to both retain significant antiproliferative activity and selectivity for the ERα and possibility to target estrogen-dependent tissues. Finally, E-OxaPs 1b and 2b are potentially promising alternatives vector complexes to target estrogen-dependent tissues.
Département de Chimie-Biologie, Groupe de Recherche en Oncologie et Endocrinologie Moléculaires, Université du Québec à Trois-Rivières, C.P. 500, Trois-Rivières, Québec, Canada G9A 5H7. Pijus.Saha@uqtr.ca
Pijus
P
Saha
Caroline
C
Descôteaux
Kevin
K
Brasseur
Sébastien
S
Fortin
Valérie
V
Leblanc
Sophie
S
Parent
Eric
E
Asselin
Gervais
G
Bérubé
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016190:Carboplatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011485:Protein Binding / Q000502:physiology; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D047628:Estrogen Receptor alpha; D004958:Estradiol; D016190:Carboplatin