Tuning the hydrolytic aqueous chemistry of osmium arene complexes with N,O-chelating ligands to achieve cancer cell cytotoxicity.
Potential biological and medical applications of organometallic complexes are hampered by a lack of knowledge of their aqueous solution chemistry. We show that the hydrolytic and aqueous solution chemistry of half-sandwich OsII arene complexes of the type [(eta6-arene)Os(XY)Cl] can be tuned with XY chelating ligands to achieve cancer cell cytoxicity comparable to carboplatin. Complexes containing arene = p-cymene, XY = N,O-chelating ligands glycinate (1), L-alaninate (2), alpha-aminobutyrate (3), beta-alaninate (4), picolinate (5), or 8-hydroxyquinolinate (7) were synthesized. Although, 1-4 and 7 hydrolyzed rapidly (<min), complexes with pi-acceptor pyridine as N-donor and carboxylate as O-donor (5 and 6) hydrolyzed much more slowly (t1/2 = 0.20 and 0.52 h, 298 K). The aqua picolinate complexes were more acidic (pKa* = 6.67, 6.33) than the other aqua adducts (pKa* = 7.17-7.71). At biological test concentrations (micromolar), the chelating ligands dissociated from complexes 1-4 to give the inert hydroxo-bridged dinuclear species [(eta6-arene)Os(mu-OH)3Os(eta6-arene)]+ (8), and these complexes were inactive toward human lung A549 and ovarian A2780 cancer cells. In contrast, 5-7 were cytotoxic, especially 6 (IC50 values of 8 and 4.2 microM). The X-ray structures of 9-ethylguanine, [(eta6-p-cym)Os(pico)(9EtG-N7)]PF6, and 9-ethyladenine, [(eta6-p-cym)Os(pico)(9EtA-N7)]PF6, adducts of 5 are reported (the first reported for G or A adducts of OsII). Crystals of the 9EtA complex contain homoadenine base pairing. The 9EtG adduct in particular exhibits remarkable aqueous kinetic stability. This work shows how the rational control of chemical reactivity (hydrolysis, acidity, formation of hydroxo-bridged dinuclear species) can allow the design of cytotoxic anticancer OsII arene complexes.
Peacock
Anna F A
AF
School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, U.K.
Parsons
Simon
S
Sadler
Peter J
PJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy; D019906:Nuclear Magnetic Resonance, Biomolecular; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009992:Osmium / Q000737:chemistry* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy; D012996:Solutions; D014867:Water / Q000737:chemistry
D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D002614:Chelating Agents; D009942:Organometallic Compounds; D012996:Solutions; D014867:Water; D009992:Osmium; D006147:Guanine; C014542:9-ethylguanine; D004247:DNA