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The effect of a bromide leaving group on the properties of nitro analogs of the duocarmycins as hypoxia-activated prodrugs and phosphate pre-prodrugs for antitumor therapy.
Stevenson, Ralph J; Denny, William A; Ashoorzadeh, Amir; Pruijn, Frederik B; van Leeuwen, Wouter F; Tercel, Moana.
Afiliação
  • Stevenson RJ; Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. r.stevenson@auckland.ac.nz
Bioorg Med Chem ; 19(20): 5989-98, 2011 Oct 15.
Article em En | MEDLINE | ID: mdl-21920763
Nitro seco analogs (nitroCBIs) of the antitumor antibiotic duocarmycins are a new class of hypoxia activated prodrugs. These compounds undergo hypoxia-selective metabolism to form potent DNA alkylating agents. A series of four nitroCBI alcohol prodrugs containing a bromide rather than chloride or sulfonate leaving group was synthesized. In assays for in vitro hypoxia-selective cytotoxicity against human tumor cell lines the two bromides with DNA minor groove binding basic side chains displayed hypoxic cytotoxicity ratios (HCRs) of 52-286 in HT29 cells and 41-43 in SiHa cells. These values compare well with a related previously reported chloride analog. The corresponding more water soluble phosphate pre-prodrugs of the bromides were synthesized and evaluated for in vivo antitumor activity against SiHa human tumor xenografts. All four phosphates, with both neutral and basic side chains, demonstrated activity providing statistically significant hypoxic log(10) cell kills of 0.87-2.80 at non-toxic doses, matching or proving superior to those of their chloride analogs.
Assuntos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Brometos / Pró-Fármacos / Antineoplásicos Alquilantes Limite: Animals / Female / Humans / Male Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2011 Tipo de documento: Article País de afiliação: Nova Zelândia

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Brometos / Pró-Fármacos / Antineoplásicos Alquilantes Limite: Animals / Female / Humans / Male Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2011 Tipo de documento: Article País de afiliação: Nova Zelândia