Tuning the hydrolytic aqueous chemistry of osmium arene complexes with N,O-chelating ligands to achieve cancer cell cytotoxicity

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Tuning the hydrolytic aqueous chemistry of osmium arene complexes with N,O-chelating ligands to achieve cancer cell cytotoxicity. / Peacock, Anna; Parsons, S; Sadler, PJ.

In: Journal of the American Chemical Society, Vol. 129, No. 11, 21.03.2007, p. 3348-3357.

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@article{9e71bc63adff4fcebb299fd33fef3ba1,
title = "Tuning the hydrolytic aqueous chemistry of osmium arene complexes with N,O-chelating ligands to achieve cancer cell cytotoxicity",
abstract = "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 Os-II arene complexes of the type [(eta(6)-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 4 hydrolyzed rapidly (<min), complexes with pi-acceptor pyridine as N-donor and carboxylate as O-donor (5 and 6) hydrolyzed much more slowly (t(1/2) = 0.20 and 0.52 h, 298 K). The aqua picolinate complexes were more acidic (pK(a)* = 6.67, 6.33) than the other aqua adducts (pK(a)* = 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 [(eta(6)-arene)Os(mu-OH)(3)Os(eta(6)-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 mu M). The X-ray structures of 9-ethylguanine, [(eta(6)-p-cym)Os(pico)(9EtG-N7)]PF6, and 9-ethyladenine, [(eta(6)-p-cym)Os(pico)(9EtA-N7)]PF6, adducts of 5 are reported (the first reported for G or A adducts of Os-II). 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 Os-II arene complexes.",
author = "Anna Peacock and S Parsons and PJ Sadler",
year = "2007",
month = mar,
day = "21",
doi = "10.1021/ja068335p",
language = "English",
volume = "129",
pages = "3348--3357",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "11",

}

RIS

TY - JOUR

T1 - Tuning the hydrolytic aqueous chemistry of osmium arene complexes with N,O-chelating ligands to achieve cancer cell cytotoxicity

AU - Peacock, Anna

AU - Parsons, S

AU - Sadler, PJ

PY - 2007/3/21

Y1 - 2007/3/21

N2 - 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 Os-II arene complexes of the type [(eta(6)-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 4 hydrolyzed rapidly (<min), complexes with pi-acceptor pyridine as N-donor and carboxylate as O-donor (5 and 6) hydrolyzed much more slowly (t(1/2) = 0.20 and 0.52 h, 298 K). The aqua picolinate complexes were more acidic (pK(a)* = 6.67, 6.33) than the other aqua adducts (pK(a)* = 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 [(eta(6)-arene)Os(mu-OH)(3)Os(eta(6)-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 mu M). The X-ray structures of 9-ethylguanine, [(eta(6)-p-cym)Os(pico)(9EtG-N7)]PF6, and 9-ethyladenine, [(eta(6)-p-cym)Os(pico)(9EtA-N7)]PF6, adducts of 5 are reported (the first reported for G or A adducts of Os-II). 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 Os-II arene complexes.

AB - 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 Os-II arene complexes of the type [(eta(6)-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 4 hydrolyzed rapidly (<min), complexes with pi-acceptor pyridine as N-donor and carboxylate as O-donor (5 and 6) hydrolyzed much more slowly (t(1/2) = 0.20 and 0.52 h, 298 K). The aqua picolinate complexes were more acidic (pK(a)* = 6.67, 6.33) than the other aqua adducts (pK(a)* = 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 [(eta(6)-arene)Os(mu-OH)(3)Os(eta(6)-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 mu M). The X-ray structures of 9-ethylguanine, [(eta(6)-p-cym)Os(pico)(9EtG-N7)]PF6, and 9-ethyladenine, [(eta(6)-p-cym)Os(pico)(9EtA-N7)]PF6, adducts of 5 are reported (the first reported for G or A adducts of Os-II). 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 Os-II arene complexes.

U2 - 10.1021/ja068335p

DO - 10.1021/ja068335p

M3 - Article

C2 - 17319668

VL - 129

SP - 3348

EP - 3357

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 11

ER -