New steroidal 7-azaindole platinum(II) antitumor complexes.
Two new steroidal 7-azaindole-based N-donor ligands 17-α-[7-azaindole-5-ethynyl]-17-β-testosterone (ET-Haza) (1) and 17-α-[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-κN,κC; 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.
Departamento de Química Inorgánica and Regional Campus of International Excellence "Campus Mare Nostrum", Universidad de Murcia and Instituto Murciano de Investigación Biosanitaria (IMIB), Spain, E-30071 Murcia, Spain.
Ana
A
Zamora
Venancio
V
Rodríguez
Natalia
N
Cutillas
Gorakh S
GS
Yellol
Arturo
A
Espinosa
Katia G
KG
Samper
Mercè
M
Capdevila
Oscar
O
Palacios
José
J
Ruiz
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009841:Oligonucleotides / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013256:Steroids / Q000737:chemistry*
C023422:7-azaindole dimer; D000970:Antineoplastic Agents; D007211:Indoles; D009841:Oligonucleotides; D009944:Organoplatinum Compounds; D013256:Steroids; D010984:Platinum; D004247:DNA; D002945:Cisplatin
Cancer cells; Cytotoxicity; DNA; Metal complex steroidal conjugate; Platinum complexes