New steroidal 7-azaindole platinum (II) antitumor complexes

被引：26
作者：
Zamora, Ana [1 ,2 ]
Rodriguez, Venancio [1 ,2 ]
Cutillas, Natalia [1 ,2 ]
Yellol, Gorakh S. [1 ,2 ]
Espinosa, Arturo [3 ]
Samper, Katia G. [4 ]
Capdevila, Merce [4 ]
Palacios, Oscar [4 ]
Ruiz, Jose [1 ,2 ]
机构：
[1] Univ Murcia, Dept Quim Inorgan, E-30071 Murcia, Spain
[2] IMIB, E-30071 Murcia, Spain
[3] Univ Murcia, Dept Quim Organ, E-30071 Murcia, Spain
[4] Univ Autonoma Barcelona, Fac Ciencies, Dept Quim, E-08193 Barcelona, Spain
来源：
JOURNAL OF INORGANIC BIOCHEMISTRY | 2013年 / 128卷
关键词：
Platinum complexes; Cytotoxicity; Metal complex steroidal conjugate; DNA; Cancer cells; ESTROGEN-RECEPTOR-ALPHA; ZETA VALENCE QUALITY; METAL-COMPLEXES; CATHEPSIN-B; BOND ORDER; IN-VITRO; HARTREE-FOCK; BASIS-SETS; CISPLATIN; INHIBITION;
D O I：
10.1016/j.jinorgbio.2013.07.010
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Two new steroidal 7-azaindole-based N-donor ligands 17-alpha-[7-azaindole-5-ethynyl]-17-beta-testosterone (ET-Haza) (1) and 17-alpha-[7-azaindole-5-ethynyl]-19-nortestosterone (LEV-Haza) (2), and two new DNA damaging warheads with an enhanced lipophilicity [Pt(dmba)Cl(L)] (dmba = N,N-dimethylbenzylamine-kappa N,kappa C; L = ET-Haza (3) and LEV-Haza (4)) have been prepared and characterized. Values of IC50 were calculated for complexes 3 and 4 against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cis) and breast cancers (T47D). At 48 h of incubation time 3 and 4 showed very low resistance factors (RF of 1) against an A2780 cell line which has acquired resistance to cisplatin, IC50 values of the new complexes towards normal human LLC-PK1 renal cells at 48 h being about double than that of cisplatin. 3 and 4 are able to react with 9-ethylguanine (9-EtG) yielding the corresponding monoadduct [Pt(dmba)(L)(9-EtG)(+) derivatives as followed by ESI-MS. Compound 3 interacts mainly with double-stranded (DS) oligonucleotides as shown by analysis with ESI-TOF-MS, being also able to displace ethidium bromide (EB) from DNA, as observed by an electrophoretic mobility study. 3 and 4 are good cathepsin B inhibitors. Theoretical calculations at the COSMO(CHCl3)/B3LYP-D/def2-TZVPPecp//B3LYP-D/def2-TZVPecp level and energy evaluations at the COSMO(CHCl3)/PWPB95-D3/def2-TZVPPecp level of theory on compound 4 and model systems have been done. (C) 2013 Elsevier Inc. All rights reserved.
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页码：48 / 56
页数：9
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