Mirror-image organometallic osmium arene iminopyridine halido complexes exhibit similar potent anticancer activity.

Ying Fu,Rina Soni,Jessica M. Hearn,Ana M. Pizarro,Abraha Habtemariam,Peter J. Sadler,Guy J. Clarkson,Luca Salassa,María J. Romero,Martin Wills

doi:10.1002/chem.201302183

Abstract

Four chiral OsII arene anticancer complexes have been isolated by fractional crystallization. The two iodido complexes, (SOs,SC)-[Os(η6-p-cym)(ImpyMe)I]PF6 (complex 2, (S)-ImpyMe: N-(2-pyridylmethylene)-(S)-1-phenylethylamine) and (ROs,RC)-[Os(η6-p-cym)(ImpyMe)I]PF6 (complex 4, (R)-ImpyMe: N-(2-pyridylmethylene)-(R)-1-phenylethylamine), showed higher anticancer activity (lower IC50 values) towards A2780 human ovarian cancer cells than cisplatin and were more active than the two chlorido derivatives, (SOs,SC)-[Os(η6-p-cym)(ImpyMe)Cl]PF6, 1, and (ROs,RC)-[Os(η6-p-cym)(ImpyMe)Cl]PF6, 3. The two iodido complexes were evaluated in the National Cancer Institute 60-cell-line screen, by using the COMPARE algorithm. This showed that the two potent iodido complexes, 2 (NSC: D-758116/1) and 4 (NSC: D-758118/1), share surprisingly similar cancer cell selectivity patterns with the anti-microtubule drug, vinblastine sulfate. However, no direct effect on tubulin polymerization was found for 2 and 4, an observation that appears to indicate a novel mechanism of action. In addition, complexes 2 and 4 demonstrated potential as transfer-hydrogenation catalysts for imine reduction.

Highlights

The U.S Food and Drug Administration (FDA) has defined strict rules for the development of new stereoisomeric drugs, especially following the tragedy of severe birth defects caused by the S isomer of thalidomide[1]
The pure chiral iminopyridine ligand ((S)- or (R)-ImpyMe: N-(2-pyridylmethylene)-(S)-1-phenylethylamine or N-(2-pyridylmethylene)-(R)-1-phenylethylamine) was reacted with the OsII dimer—[{OsACHTUNGRE(h6-p-cym)Cl2}2] or [{OsACHTUNGRE(h6-pcym)I2}2]—to form both diastereomers; the diastereomer that crystallized first was collected from each reaction and the second diastereomer was left in the mother liquor
Isolated single crystals were used for the physical and biological studies of all the four osmium complexes reported in this work. This approach to the study of chirality has been widely used on RuII and OsII arene catalysts with “piano-stool” geometry, there appears to be no report of any application in metallo-drug research

Summary

Introduction

The U.S Food and Drug Administration (FDA) has defined strict rules for the development of new stereoisomeric drugs, especially following the tragedy of severe birth defects caused by the S isomer of thalidomide[1] (originally developed as an antisedative drug, found to be an inhibitor of angiogenesis for anticancer treatment[2,3]). The fast-growing field of bioorganometallic chemistry has attracted much interest in the development of the generation of anticancer agents following the success of the platinum-based drugs cisplatin, carboplatin, and oxaliplatin.[4,5,6,7,8] Examples in-. Salassa CIC biomaGUNE Paseo Miramón 182, 20009 Donostia-San Sebastiμn (Spain). M. Hearn Warwick Systems Biology Centre, University of Warwick Gibbet Hill Road, Coventry, CV4 7AL (UK)

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Results

Conclusion