Autophagy is originally named as a process of protein recycling. It begins with sequestering cytoplasmic organelles in a membrane vacuole called autophagosome. Autophagosomes then fuse with lysosomes, where the materials inside are degraded and recycled. To date, however, little is known about the role of autophagy in cancer therapy. In this study, we present that temozolomide (TMZ), a new alkylating agent, inhibited the viability of malignant glioma cells in a dose-dependent manner and induced G2/M arrest. At a clinically achievable dose (100 microM), TMZ induced autophagy, but not apoptosis in malignant glioma cells. After the treatment with TMZ, microtubule-associated protein light-chain 3 (LC3), a mammalian homologue of Apg8p/Aut7p essential for amino-acid starvation-induced autophagy in yeast, was recruited on autophagosome membranes. When autophagy was prevented at an early stage by 3-methyladenine, a phosphatidylinositol 3-phosphate kinase inhibitor, not only the characteristic pattern of LC3 localization, but also the antitumor effect of TMZ was suppressed. On the other hand, bafilomycin A1, a specific inhibitor of vacuolar type H(+)-ATPase, that prevents autophagy at a late stage by inhibiting fusion between autophagosomes and lysosomes, sensitized tumor cells to TMZ by inducing apoptosis through activation of caspase-3 with mitochondrial and lysosomal membrane permeabilization, while LC3 localization pattern stayed the same. These results indicate that TMZ induces autophagy in malignant glioma cells. Application of an autophagy inhibitor that works after the association of LC3 with autophagosome membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ for malignant gliomas.

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Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

Two-dimensionally extended, polycyclic heteroaromatic molecules (heterocyclic nanographenes) are a highly versatile class of organic materials, applicable as functional chromophores and organic semiconductors. In this Review, we discuss the rich chemistry of large heteroaromatics, focusing on their synthesis, electronic properties, and applications in materials science. This Review summarizes the historical development and current state of the art in this rapidly expanding field of research, which has become one of the key exploration areas of modern heterocyclic chemistry.

Heterocyclic Nanographenes and Other Polycyclic Heteroaromatic Compounds: Synthetic Routes, Properties, and Applications

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

Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) occur more frequently than other types of primary central nervous system tumors, having a combined incidence of 5-8/100,000 population. Even with aggressive treatment using surgery, radiation, and chemotherapy, median reported survival is less than 1 year. Temozolomide, a new drug, has shown promise in treating malignant gliomas and other difficult-to-treat tumors. Temozolomide, a p.o. imidazotetrazine second-generation alkylating agent, is the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. In vitro, temozolomide has demonstrated schedule-dependent antitumor activity against highly resistant malignancies, including high-grade glioma. In clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O6-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma. Temozolomide has recently been approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy. Predictable bioavailability and minimal toxicity make temozolomide a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types. An overview of the mechanism of action of temozolomide and a summary of results from clinical trials in malignant glioma are presented here.

https://clincancerres.aacrjournals.org/content/clincanres/6/7/2585.full.pdf

Temozolomide and treatment of malignant glioma.

Stereoselective Addition to N-Activated Pyridines James A. Bull,‡ James J. Mousseau, Guillaume Pelletier,† and Andre ́ B. Charette*,† †Department of Chemistry, Universite ́ de Montreál, P.O. Box 6128, Station Downtown, Montreál, Queb́ec, Canada H3C 3J7 ‡Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, U.K. Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition to N-Activated Pyridines

Interaction of 5-diazoimidazole-4-carboxamide and alkyl and aryl isocyanates in the dark affords 8-carbamoyl-3-substituted-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-on es. In cold methanol or ethanol, the 3-(2-chloroethyl) derivative 7a decomposes to afford 2-azahypoxanthine (14) and methyl and ethyl N-(2-chloroethyl)carbamates, respectively. Compound 7a has curative activity against L-1210 and P388 leukemia and may act as a prodrug modification of the acyclic triazene 5-[3-(2-chloroethyl)triazen-1-yl]imidazole-4-carboxamide (MCTIC), since it ring opens to form the triazene in aqueous sodium carbonate.

Antitumor imidazotetrazines. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one , a novel broad-spectrum antitumor agent.

N-oxides and related compounds—XXXIX

The systematic variation of the potent antitumor agent mitozolomide (1) is extended to cover alteration of substituents at positions 6 and 8 and to change the imidazo[5,1-d]-1,2,3,5-tetrazinone (1) skeleton to the isomeric pyrazolo-[5,1-d]-1,2,3,5-tetrazinone (17) skeleton. The series of eight 6-alkyl and 6-aralkyl derivatives of 1 showed optimal antitumor activity when the group was small or linear, but activity diminished as size and branching of this substituent increased. This may reflect altered transport characteristics, or failure of the enlarged derivatives to fit a binding site, or possibly a reduced tendency for the derivatives having bulky groups at position 6 to hydrolytically generate the putatively active triazenes (21). Testing of 14 derivatives of 1 differently substituted at position 8 revealed a complex structure-activity relationship, with good antitumor activity obtained for carbamoyl and sulfamoyl groups bearing small substituents. The 8-methylsulfonyl compound had noteworthy activity, but the 8-cyano, 8-nitro, and 8-phenyl derivatives were devoid of useful antitumor activity in these tests. From the limited number of pyrazolotetrazinones (17) reported here, it is suggested that the same conclusions as regards activity also hold true for this ring system.

Antitumor imidazotetrazines. 14. Synthesis and antitumor activity of 6- and 8-substituted imidazo[5,1-d]-1,2,3,5-tetrazinones and 8-substituted pyrazolo[5,1-d]-1,2,3,5-tetrazinones

8-Carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H) -one (mitozolomide) demonstrates curative action against a range of murine tumor model systems At single doses of between 20 and 40 mg/kg, the latter of which approximates the 10% lethal dose value in mice, the compound elicited cures against the L1210 and P388 leukemias irrespective of the route of tumor and/or drug administration; in these tests, animals receiving 10(5) cells ip survived greater than 60 days after treatment Potent effects were also observed against the TLX5 lymphoma (sc) and B16 melanoma (ip) In other experiments, 7 of 10 animals implanted with 2 X 10(5) Lewis lung carcinoma cells survived greater than 60 days while 10 of 10 animals survived greater than 60 days after implantation of the Colon 26 tumor Potent inhibition of the solid tumor models was also observed with complete cures of the Colon 38, M5076 sarcoma, and ADJ/PC6A plasmacytoma In cross-resistance studies, the compound was ineffective against an L1210 leukemia made resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea and against a TLX5 lymphoma resistant to dimethyltriazenes but cured animals bearing the L1210 leukemia with derived resistance to cyclophosphamide

https://cancerres.aacrjournals.org/content/canres/45/7/3008.full.pdf

Experimental antitumor activity against murine tumor model systems of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one (mitozolomide), a novel broad-spectrum agent

Photocyclisation of 1-(2-pyridyl)-2-arylpyridiniums yields benzo[c]pyrido[1,2-a]-1,8-naphthyridinylinium cations. Photobiscyclisation of 1,2,6-triarylpyridiniums gives benzo[8,9]quinolizino[4,5,6,7-fed]phenanthridinylium cations and their 9-aza-derivatives. Electron donor substituents tend to lower the yields which are otherwise high. The structures are supported by X-ray crystallographic analysis and by ultraviolet and n.m.r. spectra.

Edward Lunt

Papers

Antitumor imidazotetrazines. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one , a novel broad-spectrum antitumor agent.

N-oxides and related compounds—XXXIX

Antitumor imidazotetrazines. 14. Synthesis and antitumor activity of 6- and 8-substituted imidazo[5,1-d]-1,2,3,5-tetrazinones and 8-substituted pyrazolo[5,1-d]-1,2,3,5-tetrazinones

Experimental antitumor activity against murine tumor model systems of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one (mitozolomide), a novel broad-spectrum agent

The photocyclisation of 1,2-Ciarylpyridinium cations and the photobiscyclisation of 1,2,6-triarylpyridinium cations