Modulatory effect of axial and equatorial ligands on antitumor activities of trans-1R,2R-diaminocyclohexane platinum(IV) complexes.
Acquired drug resistance is a major drawback of using cisplatin in the treatment of cancer; however, platinum analogs containing the 1,2-diaminocyclohexane (DACH) ligand can overcome this resistance. DACH can exist as the trans-1R,2R, trans-1S,2S or cis isomer, and we have previously established that the R,R form of DACH-Pt(II) complex is in general superior. Here, we have examined if specific axial and/or equatorial ligands attached to a platinum(IV) center can modulate the antitumor activities of R,R-DACH-Pt complexes in murine tumor models in vivo. Four series of R,R-DACH-Pt complexes were synthesized, with each series consisting of one platinum(II) complex and three corresponding platinum(IV) analogs, each differing by the chemical nature of the axial ligand (chloro, hydroxo or acetato). Combination of axial chloro with equatorial chloro (Cl2Cl2), 1,1-cyclobutanedicarboxylato (Cl2CBDCA), tartronato (Cl2Tart) or methylmalonato (Cl2MeMal) gave activities which were similar to or greater than those of the corresponding platinum(II) complex in the cisplatin-sensitive L1210/0 or cisplatin-resistant L1210/DDP leukemia and solid M5076 reticulosarcoma models. The exception was the complex Cl2Cl2 in the M5076 model, which was 2-fold less sensitive to this platinum(IV) complex than to the corresponding platinum(II) analog. Axial hydroxo or acetato platinum(IV) complexes were effective in combination with equatorial chloro ([OH]2Cl2 or Ac2Cl2) or tartronato ([OH]2Tart or Ac2Tart) against L1210/0, L1210/DDP and M5076 cells, but effective only against M5076 cells when combined with equatorial 1,1-cyclobutanedicarboxylato (CBDCA) or methylmalonato. The results demonstrated a profound effect of axial and equatorial ligands on the antitumor activities of R,R-DACH-Pt(IV) complexes. Furthermore, these modulatory effects could be influenced strongly by the tumor model. The interesting finding from this structure-activity study was the emergence of R,R-DACH([OH]2Cl2)Pt(IV) complex as a 'lead' analog worthy of further exploration.
Siddik
Z H
ZH
Department of Clinical Investigation, University of Texas M.D. Anderson, Cancer Center, Houston 77030.
al-Baker
S
S
Thai
G
G
Khokhar
A R
AR
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D008024:Ligands; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D002945:Cisplatin