Richard T. Wheelhouse

Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials

*Department of Medical Oncology, Chafing Cross Hospital, Fulham Palace Road, London W6 8RF, U.K. t Cancer Research Campaign Experimental Cancer Chemotherapy Research Group, Cancer Research Laboratories, Department of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 ZRD, U.K.

G-quadruplexes as targets for drug design

Drugs Dynamics Institute, College of Pharmacy, University of Texas at Austin, Austin, TX 78712-7074, U.S.A.

Glioblastoma Multiforme Therapy and Mechanisms of Resistance

G-quadruplexes are a family of secondary DNA structures formed in the presence of monovalent cations that consist of four-stranded structures in which Hoogsteen base-pairing stabilizes G-tetrad structures. These structures are proposed to exist in vivo, although direct confirmatory evidence is lacking. Guanine-rich regions of DNA capable of forming G-quadruplex structures are found in a variety of chromosomal regions, including telomeres and promoter regions of DNA. In this review, we describe the design of three separate groups of G-quadruplex-interactive compounds and their interaction with G-quadruplex DNA. Using the first group of compounds (anthraquinones), we describe experiments that provide the proof of concept that a G-quadruplex is required for inhibition of telomerase. Using the second group of compounds (perylenes), we describe the structure of a G-quadruplex-ligand complex and its effect on the dynamics of formation and enzymatic unwinding of the quadruplex. For the third group of compounds (porphyrins), we describe the experiments that relate the biological effects to their interactions with G-quadruplexes.

A novel, high-yielding synthesis of meso-substituted porphyrins via the direct arylation of porphine

Glioblastoma multiforme (GBM) is a grade IV brain tumor characterized by a heterogeneous population of cells that are highly infiltrative, angiogenic and resistant to chemotherapy. The current standard of care, comprised of surgical resection followed by radiation and the chemotherapeutic agent temozolomide, only provides patients with a 12–14 month survival period post-diagnosis. Long-term survival for GBM patients remains uncommon as cells with intrinsic or acquired resistance to treatment repopulate the tumor. In this review we will describe the mechanisms of resistance, and how they may be overcome to improve the survival of GBM patients by implementing novel chemotherapy drugs, new drug combinations and new approaches relating to DNA damage, angiogenesis and autophagy.

Antitumour imidazotetrazines. Part 39. Synthesis of bis(imidazotetrazine)s with saturated spacer groups

A new method for the synthesis of meso-substituted porphyrins is described: reaction of 5,10,15,20-tetrabromoporphine magnesium complex with aryl or heteroaryl boronic acids in the presence of Pd(PPh3)4 gave meso-substituted porphyrins in yields up to 70%.

Synthesis and Quantitative Structure–Activity Relationship of Imidazotetrazine Prodrugs with Activity Independent of O6-Methylguanine-DNA-methyltransferase, DNA Mismatch Repair, and p53

Bis(imidazotetrazine)s (16), related in structure to the antitumour agents mitozolomide (1a) and temozolomide (1b), but linked through the N(3)–N(3′) atoms of the imidazo[5,1-d][1,2,3,5]tetrazine ring-systems, are prepared by interaction of 5-diazoimidazole-4-carboxamide (8) and diisocyanates (15). The presence of the polymethylene linker with/without sulfur and oxygen heteroatoms does not substantially affect the acid stability, base-catalysed decomposition, antitumour activity or DNA base alkylation preference characteristic of the unlinked imidazotetrazines mitozolomide and temozolomide.

Decomposition of the antitumour drug temozolomide in deuteriated phosphate buffer: methyl group transfer is accompanied by deuterium exchange

The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR, and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bifunctional analogues are reported, and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bifunctional congener as optimized for potency, MGMT-independence, and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development, and their improved in vitro activity validates the principles on which they were designed.

Motion of polyammonium ions on aqueous solutions of DNA

The antitumour prodrug temozolomide 1 undergoes ring-opening in deuteriated phosphate buffer; deuterium incorporation into the methyl group transferred from the reactive species 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC)2has been monitored by observing D–H and P–H couplings in the NMR spectra of the products.

Inhibition of cobalamin-dependent methionine synthase by substituted benzo-fused heterocycles

Abstract Magnetic resonance techniques have been used to establish or confirm that (i) various polyamines are present almost completely as polyammonium cations at pH 7, (ii) that these have the very high affinity for DNA expected between a polycation and polyanion, and (iii) that this is a loose electrostatic interaction which does not significantly hinder motion (rotational and translational) of the cations close to DNA, and hence that migration of the polyammonium ions along the DNA must be extremely rapid.

The Medicinal Chemistry of Imidazotetrazine Prodrugs

The cobalamin–dependent cytosolic enzyme, methionine synthase (EC.2.1.1.13), catalyzes the remethylation of homocysteine to methionine using 5‐methyltetrahydrofolate as the methyl donor. The products of this remethylation – methionine and tetrahydrofolate – participate in the active methionine and folate pathways. Impaired methionine synthase activity has been implicated in the pathogenesis of anaemias, cancer and neurological disorders. Although the need for potent and specific inhibitors of methionine synthase has been recognized, there is a lack of such agents. In this study, we designed, synthesized and evaluated the inhibitory activity of a series of substituted benzimidazoles and small benzothiadiazoles. Kinetic analysis revealed that the benzimidazoles act as competitive inhibitors of the rat liver methionine synthase, whilst the most active benzothiadiazole (IC50 = 80 µm) exhibited characteristics of uncompetitive inhibition. A model of the methyltetrahydrofolate‐binding site of the rat liver methionine synthase was constructed; docking experiments were designed to elucidate, in greater detail, the binding mode and reveal structural requirements for the design of inhibitors of methionine synthase. Our results indicate that the potency of the tested compounds is related to a planar region of the inhibitor that can be positioned in the centre of the active site, the presence of a nitro functional group and two or three probable hydrogen‐bonding interactions.