85622-95-3Relevant academic research and scientific papers
Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual-Targeting HDAC Inhibitors and HDAC Degraders (PROTACs)
Bandolik, Jan J.,Bhatia, Sanil,Borkhardt, Arndt,Hamacher, Alexandra,Hansen, Finn K.,Kassack, Matthias U.,Meiler, Jens,Roatsch, Martin,S?nnichsen, Melf,Sch?ler, Andrea,Schoeder, Clara T.,Sinatra, Laura
supporting information, p. 22494 - 22499 (2020/10/12)
Inhibition of more than one cancer-related pathway by multi-target agents is an emerging approach in modern anticancer drug discovery. Here, based on the well-established synergy between histone deacetylase inhibitors (HDACi) and alkylating agents, we present the discovery of a series of alkylating HDACi using a pharmacophore-linking strategy. For the parallel synthesis of the target compounds, we developed an efficient solid-phase-supported protocol using hydroxamic acids immobilized on resins (HAIRs) as stable and versatile building blocks for the preparation of functionalized HDACi. The most promising compound, 3 n, was significantly more active in apoptosis induction, activation of caspase 3/7, and formation of DNA damage (γ-H2AX) than the sum of the activities of either active principle alone. Furthermore, to demonstrate the utility of our preloaded resins, the HAIR approach was successfully extended to the synthesis of a proof-of-concept proteolysis-targeting chimera (PROTAC), which efficiently degrades histone deacetylases.
IMIDAZOTETRAZINONE-BASED COMBI-MOLECULES
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Page/Page column 6-7, (2012/11/13)
A series of new chemical agents that demonstrate anti-tumor activity are described herein. The new chemical agents exhibit a dual mode of anti-tumor action: blocking epidermal growth factor receptor (EGFR) mediated signal transduction and damaging DNA by alkylation.
Antitumour imidazotetrazines. Part 36. Conversion of 5-aminoimidazole-4-carboxamide to imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-ones and imidazo[1,5-a][1,3,5]triazin-4(3H)-ones related in structure to the antitumour agents temozolomide and mitozolomide
Wang, Yongfeng,Wheelhouse, Richard T.,Zhao, Linxiang,Langnel, David A. F.,Stevens, Malcolm F. G.
, p. 1669 - 1675 (2007/10/03)
Novel 3-substituted imidazo[5,1-d][1,2,3,5]tetrazinones 3 have been prepared by two routes: reaction of 5-diazoimidazole-4-carboxamide 2 and isocyanates, and nitrosative cyclisation of 5-amino-1-carbamoylimidazole-4-carboxamides 7. The latter cyclisations do not proceed efficiently when the 1-carbamoyl group bears an electron-donating alkyl group. 5-Amino-1-carbamoylimidazole-4-carboxamides 7 cyclise with triethyl orthoformate or triethyl orthobenzoate to yield imidazo[1,5-a][1,3,5]triazinones 15. A 1H NMR study of the decomposition of 8-carbamoyl-3-ethylimidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one 3c in deuteriated phosphate buffer has shown that its ethylating capacity is attenuated by the unproductive generation of ethene. This observation explains why the ethylimidazotetrazine possesses weaker antitumour properties than the clinically-used congener temozolomide 3a.
A new route to the antitumour drug temozolomide, but not thiotemozolomide
Wang, Yongfeng,Lowe, Philip R.,Thomson, William T.,Clark, Jonathan,Stevens, Malcolm F. G.
, p. 363 - 364 (2007/10/03)
Interaction of 5-aminoimidazole-4-carboxamide with alkyl isocyanates yields N-substituted 1-carbamoylimidazoles which can be cyclised to imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-ones, including temozolomide 3a, on nitrosation; a similar reaction with methyl isothiocyanate, followed by nitrosation, affords the nitrosomethylamino derivative 11 of a new ring-system, imidazo[l,5-b][1,2,4]thiadiazole.
TETRAZINE DERIVATIVES
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, (2008/06/13)
[3H]-Imidazo[5,1-d] -1,2,3,5-tetrazin-4-one derivatives of the formula:wherein R1represents hydrogen, or an alkyl, alkenyl or alkynyl group containing up to 6 carbon atoms, each such group being unsubstituted or substituted by from one to three substituents selected from halogen atoms, alkoxy, alkylthio, alkylsulphinyl and alkylsulphonyl groups containing up to 4 carbon atoms, and optionally substituted phenyl groups, or R1represents a cycloalkyl group containing from 3 to 8 carbon atoms, and R2 represents a carbamoyl group optionally N-substituted by one or two groups selected ftom alkyl and alkenyl groups containing up to 4 carbon atoms, and cycloalkyl groups containing 3 to 8 carbon atoms, are new therapeutically useful compounds possessing antineoplastic and immunomodulatory activity
ANTITUMOUR IMIDAZOTETRAZINES. PART 5. CRYSTAL AND MOLECULAR STRUCTURE OF 8-CARBAMOYL-3-(2-CHLOROETHYL)IMIDAZO-1,2,3,5-TETRAZIN-4(3H)-ONE (MITOZOLOMIDE)
Lowe, Philip R.,Schwalbe, Carl H.,Stevens, Malcolm F.G.
, p. 357 - 362 (2007/10/02)
The structure of the novel bicyclic antitumour agent 8-carbamoyl-3-(2-chloroethyl)imidazo-1,2,3,5-tertazin-4(3H)-one (Mitozolomide) has been investigated by single-crystal X-ray diffraction methods.The compound crystallizes in the triclinic space group P1/ in a cell of dimensions a = 7.003(4), b = 8.680(4), c = 16.041(9) Angstroem, α = 93.76(5), β = 93.99(5), γ = 92.08(7)deg with z = 4.The structure was solved by direct methods and refined using full-matrix least-squares calculations, which at convergence produced a final R index of 0.052 for the 3 244 observed data.The two independent molecules per asymmetric unit are rotamers about the C(8)-C(81) and C(8)'-C(81)' bonds, the orientation of the carbamoyl group in one rotamer facilitating an intramolecular hydrogen bond of the type N-H...N.With the exception of the chloroethyl side chain, both molecules are approximately planar and intermolecular hydrogen bonds hold groups of four molecules together around the centre of symmetry.
Antitumor Imidazotetrazines. 1. Synthesis and Chemistry of 8-Carbamoyl-3-(2-chloroethyl)imidazo-1,2,3,5-tetrazin-4(3H)-one, a Novel Broad-Spectrum Antitumor Agent
Stevens, Malcolm F. G.,Hickman, John A.,Stone, Robert,Gibson, Neil W.,Baig, Ghouse Unissa,et al.
, p. 196 - 201 (2007/10/02)
Interaction of 5-diazoimidazole-4-carboxamide and alkyl and aryl isocyanates in the dark affords 8-carbamoyl-3-substituted-imidazo-1,2,3,5-tetrazin-4(3H)-ones.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-imidazole-4-carboxamide (MCTIC), since it ring opens to form the triazene in aqueous sodium carbonate.
