The Medicinal Chemistry of Imidazotetrazine Prodrugs

Abstract

Temozolomide (TMZ) is the standard first line treatment for malignant glioma, reaching “blockbuster” status in 2010, yet it remains the only drug in its class. The main constraints on the clinical effectiveness of TMZ therapy are its requirement for active DNA mismatch repair (MMR) proteins for activity, and inherent resistance through O6-methyl guanine-DNA methyl transferase (MGMT) activity. Moreover, acquired resistance, due to MMR mutation, results in aggressive TMZ-resistant tumour regrowth following good initial responses. Much of the attraction in TMZ as a drug lies in its PK/PD properties: it is acid stable and has 100% oral bioavailability; it also has excellent distribution properties, crosses the blood-brain barrier, and there is direct evidence of tumour localisation. This review seeks to unravel some of the mysteries of the imidazotetrazine class of compounds to which TMZ belongs. In addition to an overview of different synthetic strategies, we explore the somewhat unusual chemical reactivity of the imidazotetrazines, probing their mechanisms of reaction, examining which attributes are required for an active drug molecule and reviewing the use of this combined knowledge towards the development of new and improved anti-cancer agents.

Temozolomide resistance in glioblastoma multiforme

“…Temozolomide (TMZ) is an imidazotetrazine derivative of the alkylating agent dacarbazine and a prodrug of the anti-cancer drug Temodar. 1 The chemical name of TMZ is 3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide ( Fig. 1 ).…”

Synthesis and antitumor evaluation of some new derivatives and fused heterocyclic compounds derived from thieno[2,3‐b]pyridine

“… Besides, pyrazolotriazine derivatives were indicated to possess marked anticancer activities, especially against both breast cancer MCF‐7 and liver cancer HepG‐2 cell lines . Moreover, pyrazolotetrazinone was reported to exhibit excellent antineoplastic activity . The aforementioned biological activities prompted us to construct novel heterocyclic compounds utilizing thieno[2,3‐ b ]pyridine as a building block to explore promising anticancer compounds.…”

“…[9] Moreover, pyrazolotetrazinone was reported to exhibit excellent antineoplastic activity. [10] The aforementioned biological activities prompted us to construct novel heterocyclic compounds utilizing thieno [2,3-b]pyridine as a building block to explore promising anticancer compounds.…”

On the Critical Issues in Temozolomide Research in Glioblastoma: Clinically Relevant Concentrations and MGMT-independent Resistance

“…In the end, it should be emphasized that the high rate of failure in glioblastoma clinical trials assessing targeted drugs [12], as well as pharmaceutically important features of TMZ such as acid stability, oral bioavailability, absorption, hydrolysis kinetics, metabolic half-life, biodistribution, and blood-brain barrier penetration [20], rather than the satisfactory therapeutic efficiency cemented TMZ prescription for glioblastoma patients worldwide. Irrespective of cytostatic and/or cytotoxic effects of TMZ at clinically relevant low concentrations in in vitro and in vivo models, its therapeutic efficiency even in patients with MGMT-methylated tumors is limited, clearly suggesting that alternative or additional therapeutic approaches are urgently needed [12].…”