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.
Highlights
Imidazotetrazines are a class of bicyclic aromatic heterocycles, exemplified by the DNA methylating agent, temozolomide (Temodar®, Temodal®, TMZ, 1a)
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
The principal constraints on TMZ efficacy are the dependence on mismatch repair (MMR) and resistance caused by methyl guanine-DNA methyl transferase (MGMT), the result of which is that the number of tumours able to respond to TMZ therapy is limited; current efforts in the design of new analogues seek to bypass these limitations
Summary
Imidazotetrazines are a class of bicyclic aromatic heterocycles, exemplified by the DNA methylating agent, temozolomide (Temodar®, Temodal®, TMZ, 1a). In this review we will explore the reasons for this and what makes TMZ special, along with surveying current efforts to achieve new effective drugs in this class. The 3-haloethyl analogues had good activity, the 3-methyl was of moderate effectiveness but other analogues, as exemplified by the 3-ethyl, were inactive (Table 1) [9]. The solution to this conundrum and the vision to design active new analogues arose from detailed definition of the mechanism of prodrug activation using kinetic NMR experiments. TMZ entered clinical trials before the final details of prodrug activation chemistry were elucidated.
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