- Validated spectral manipulations for determination of an anti-neoplastic drug and its related impurities including its hazardous degradation product
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Innovative and specific double dual wavelength, dual ratio subtraction spectrophotometric methods were carried out along with a successive ratio subtraction spectrophotometric method for determination of dacarbazine and its related impurities including toxic and hazardous ones. For determination of dacarbazine by the double dual wavelength method, the absorbance differences between 323 and 350 nm of the zero order absorption spectra of dacarbazine were used. The values of absorbance difference between 267.2 and 286.2 nm of the zero order spectra of 5-amino-imidazole-4 carboxamide were used for its determination by the dual ratio subtraction method. The zero order absorption spectrum of 2-azahypoxanthine at 235 nm was used for its determination after applying the successive ratio subtraction method. ICH guidelines were followed for validation of the developed methods, where linear relationships were obtained in the range of 4-20, 1-16, and 2-20 μg mL?1for dacarbazine, 5-amino imidazole-4-carboxamide and 2-azahypoxanthine, respectively. Accurate, precise, and specific results were obtained upon applying the proposed methods according to ICH guidelines. Furthermore, the developed methods were successfully applied for determination of dacarbazine in its pharmaceutical formulation. Comparing the results of the developed methods with those of the official USP spectrophotometric method statistically showed no significant difference. The developed methods don't need any sophisticated techniques so they are considered cost effective methods. Moreover, the introduced methods have the advantages of being green where water was used as a solvent. The methods proved to be more economic, fast and simple than other reported HPLC methods.
- Abdelaleem, Eglal A.,Emam, Aml A.,Hassan, Eman S.,Naguib, Ibrahim A.
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p. 21332 - 21342
(2021/07/01)
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- Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual-Targeting HDAC Inhibitors and HDAC Degraders (PROTACs)
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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.
- 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
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supporting information
p. 22494 - 22499
(2020/10/12)
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- Biosynthesis of the Fairy Chemicals, 2-Azahypoxanthine and Imidazole-4-carboxamide, in the Fairy Ring-Forming Fungus Lepista sordida
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Fairy rings resulting from a fungus-plant interaction appear worldwide. 2-Azahypoxanthine (AHX) and imidazole-4-carboxamide (ICA) were first isolated from the culture broth of one of the fairy ring-forming fungi, Lepista sordida. Afterward, a common metabolite of AHX in plants, 2-aza-8-oxohypoxanthine (AOH), was found in AHX-treated rice. The biosynthetic pathway of the three compounds that are named as fairy chemicals (FCs) in plants has been partially elucidated; however, that in mushrooms remains unknown. In this study, it was revealed that the carbon skeletons of AHX and ICA were constructed from Gly in L. sordida mycelia and the fungus metabolized 5-aminoimidazole-4-carboxamide (AICA) to both of the compounds. These results indicated that FCs were biosynthesized by a diversion of the purine metabolic pathway in L. sordida mycelia, similar to that in plants. Furthermore, we showed that recombinant adenine phosphoribosyltransferase (APRT) catalyzed reversible interconversion not only between 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranosyl 5′-monophosphate (AICAR) and AICA but also between ICA-ribotide (ICAR) and ICA. Furthermore, the presence of ICAR in L. sordida mycelia was proven for the first time by LC-MS/MS detection, and this study provided the first report that there was a novel metabolic pathway of ICA in which its ribotide was an intermediate in the fungus.
- Asakawa, Tomohiro,Choi, Jae-Hoon,Hirai, Hirofumi,Inai, Makoto,Ito, Akinobu,Kan, Toshiyuki,Kawagishi, Hirokazu,Kotajima, Mihaya,Ouchi, Hitoshi,Takemura, Hirohide,Tokuyama, Shinji,Wu, Jing
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p. 2469 - 2476
(2020/08/24)
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- Antitumor imidazo[5,1-d]-1,2,3,5-tetrazines: compounds modified at the 3-position overcome resistance in human glioblastoma cell lines
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Synthetic routes to 3-substituted imidazo[5,1-d]-1,2,3,5-tetrazines structurally related to temozolomide were explored. Interaction of 4-diazoimidazole-5-carboxamide with an isocyanate afforded high product yields when the isocyanate was available in acceptable purity. Alternatively, alkylation of the nor-temozolomide anion afforded high yields of new imidazotetrazines. Several compounds, evaluated against a panel containing matched MGMT± glioma cell lines, showed equal inhibitory activity irrespective of MGMT status; the N3-propargyl-imidazotetrazine (10m) was prioritised as an alternative to temozolomide able to bypass drug-resistance mechanisms. In Taq polymerase assays 10m, like temozolomide and its ring-opened counterpart MTIC, alkylated DNA at clusters of three and five guanine residues; covalent modification of N-7 sites of guanine were detected in piperidine cleavage assays. Compound 10m did not cross-link DNA but induced double-strand breaks evidenced by γ-H2AX detection. Propargyl-substituted imidazotriazene (13g), showed comparable activity to 10m indicating that ring-opening of the bicyclic nucleus of novel imidazotetrazine is probably required for activity.
- Cousin, David,Zhang, Jihong,Hummersone, Marc G.,Matthews, Charles S.,Frigerio, Mark,Bradshaw, Tracey D.,Stevens, Malcolm F. G.
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p. 2332 - 2343
(2016/12/18)
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- Practical synthesis of natural plant-growth regulator 2-azahypoxanthine, its derivatives, and biotin-labeled probes
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We describe a practical, large-scale synthesis of the "fairy- ring" plant-growth regulator 2-azahypoxanthine (AHX), and its biologically active hydroxyl metabolite (AOH) and riboside derivative (AHXr). AHXr, a biosynthetic intermediate, was synthesized from inosine via a biomimetic route. Biotinylated derivatives of AHX and AHXr were also synthesized as probes for mechanistic studies. This journal is the Partner Organisations 2014.
- Ikeuchi, Kazutada,Fujii, Ryosuke,Sugiyama, Shimpei,Asakawa, Tomohiro,Inai, Makoto,Hamashima, Yoshitaka,Choi, Jae-Hoon,Suzuki, Tomohiro,Kawagishi, Hirokazu,Kan, Toshiyuki
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supporting information
p. 3813 - 3815
(2014/06/09)
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- An efficient and practical radiosynthesis of [11C]temozolomide
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Temozolomide (TMZ) is a prodrug for an alkylating agent used for the treatment of malignant brain tumors. A positron emitting version, [ 11C]TMZ, has been utilized to help elucidate the mechanism and biodistribution of TMZ. Challenges in [11C]TMZ synthesis and reformulation make it difficult for routine production. A highly reproducible one-pot radiosynthesis of [11C]TMZ with a radiochemical yield of 17 ± 5% and ≥97% radiochemical purity is reported.
- Moseley, Christian K.,Carlin, Stephen M.,Neelamegam, Ramesh,Hooker, Jacob M.
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supporting information
p. 5872 - 5875
(2013/02/23)
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- PROCESS FOR THE PREPARATION OF TETRAZINE DERIVATIVES
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The present invention provides a process for the preparation of a tetrazine derivative of formula (I), or a pharmaceutically acceptable salt thereof wherein R1 represents a hydrogen atom, a straight or branched C1-C6 alkyl group, C2-C6 alkenyl group or C2-C6 alkynyl group, which C1-C6 alkyl group, C2-C6 alkenyl group and C2-C6 alkynyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms, straight or branched C1-C4 alkoxy groups, C1-C4 alkylthio groups, C1-C4 alkylsulphinyl groups, C1-C4 alkylsulphonyl groups and phenyl groups, which phenyl groups are unsubstituted or substituted with one or more substituents selected from C1-C4 alkyl groups, C1-C4 alkoxy groups and nitro groups; or R1 represents a C3-C8 cycloalkyl group; and R2 represents a group of formula —(C═O)NR3R4, wherein R3 and R4 are independently selected from hydrogen atoms, C1-C4 alkyl groups, C2-C4 alkenyl groups and C3-C8 cycloalkyl groups, which process comprises: i) providing a compound N of formula (III), wherein R1 is as defined; R1—N═C═O ii) absorbing the compound of formula (III) into a solvent to obtain a solution of the compound of formula (III); iii) adding to the thus obtained solution a compound of formula (II), to obtain a compound of formula (I), as defined above, wherein R2 is as defined above; iv) decomposing any excess compound of formula (III) remaining by addition of water; and v) optionally salifying the thus obtained compound with a pharmaceutically acceptable acid, or base.
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- PROCESS FOR THE PREPARATION OF TETRAZINE DERIVATIVES
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The present invention provides a process for the preparation of a tetrazine derivative of formula (I), or a pharmaceutically acceptable salt thereof wherein R1 represents a hydrogen atom, a straight or branched C1-C6 alkyl group, C2-C6 alkenyl group or C2-C6 alkynyl group, which C1-C6 alkyl group, C2-C6 alkenyl group and C2-C6 alkynyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms, straight or branched C1-C4 alkoxy groups, C1-C4 alkylthio groups, C1-C4 alkylsulphinyl groups, C1-C4 alkylsulphonyl groups and phenyl groups, which phenyl groups are unsubstituted or substituted with one or more substituents selected from C1-C4 alkyl groups, C1-C4 alkoxy groups and nitro groups; or R1 represents a C3-C8 cycloalkyl group; and R2 represents a group of formula -(C=O)NR3R4, wherein R3 and R4 are independently selected from hydrogen atoms, C1-C4 alkyl groups, C2-C4 alkenyl groups and C3-C8 cycloalkyl groups, which process comprises: i) providing a compound of formula (III), wherein R1 is as defined; R1-N=C=O ii) absorbing the compound of formula (III) into a solvent to obtain a solution of the compound of formula (III); iii) adding to the thus obtained solution a compound of formula (II), to obtain a compound of formula (I), as defined above, wherein R2 is as defined above; iv) decomposing any excess compound of formula (III) remaining by addition of water; and v) optionally salifying the thus obtained compound with a pharmaceutically acceptable acid, or base.
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Page/Page column 13-14
(2010/07/10)
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- Synthesis and antitumor activity of 3-Methyl-4-oxo-3,4-dihydroimidazo [5,1-d][1,2,3,5]tetrazine-8-carboxylates and -carboxamides
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Seventeen novel 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine- 8-carboxylate and -carboxamide derivatives were synthesized and evaluated for their growth inhibition in seven human solid tumor and a human leukemia HL-60 cell lines. Compound IVa showed more activity than the other compounds and the positive control temozolomide. In the presence of 40 μg/mL of IVa, the survival rate of all tested tumor cells was less than 10%. Esters displayed more potent antitumour activity than amides and temozolomide against HL-60 cells. These compounds also exhibited considerably enhanced water-solubility.
- Liu, Dan,Yang, Jian-Guo,Cheng, Jie,Zhao, Lin-Xiang
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scheme or table
p. 9427 - 9436
(2011/03/22)
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- PROCESS FOR PREPARING TEMOZOLOMIDE
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The present invention relates to a process for preparing temozolomide.
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Page/Page column 4
(2008/06/13)
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- Synthesis and properties of 5-diazoimidazoles and imidazolyl-5-diazonium salts
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Diazotization of 4-R-5-aminoimidazoles (R = CONHAr, CONHAIk, morpholinocarbonyl, or piperidinocarbonyl) with sodium nitrite in aqueous solutions of mineral acids afforded the corresponding 5-diazoimidazoles, whereas the reactions in concentrated tetrafluoroboric acid produced imidazolyl-5-diazonium salts. In the solid phase, diazonium salts are transformed into the corresponding diazo compounds.
- Sadchikova,Mokrushin
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p. 1600 - 1605
(2007/10/03)
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- Synthetic studies of 8-carbamoylimidazo-[5,1-D]-1,2,3,5-tetrazin-4(3H)-one: A key derivative of antitumor drug temozolomide
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5-Diazoimidazole-4-carboxamide 4 reacted with trimethylsilyl isocyanate in acetonitrile to afford 8-carbamoylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one 1, which was undergoing a methylation to give antitumour drug temozolomide 2; while 1,5-dicarbamoyl aminoimidazole 6 failed in an azo-cyclization to give 1 but accomplished a carbon-cyclization to produce 8-carbamoylimidazo[1,5-a] s-triazin-4(3H)-one 7.
- Wang,Stevens
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p. 185 - 188
(2007/10/03)
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- Antitumour Imidazotetrazines. Part 12. Reactions of Mitozolomide and its 3-Alkyl Congeners with Oxygen, Nitrogen, Halogen, and Carbon Nucleophiles
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Mitozolomide (1) and its 3-alkyl congeners ring-open in aqueous sodium carbonate to form 5-(3-alkyltriazen-1-yl)imidazole-4-carboxamides.The 3-methyl and 3-ethyl analogues of mitozolomide decompose in alcohols to form 2-azahypoxanthine and 5-amino-1-alkoxycarbonylimidazole-4-carboxamides.In hydrazine hydrate mitozolomide yields, principally, 5-azidoimidazole-4-carboxamide, whereas the 3-alkyl-derivatives form 5-amino-4-carbamoylimidazole-1-carbohydrazide. 5-Diazoimidazole-4-carboxamide, generated by thermolysis of mitozolomide in acetic acid or pyridine, can be trapped by reactive methylenic ketones, nitriles or esters to afford imidazotriazines.
- Baig, Ghouse Unissa,Stevens, Malcolm F. G.
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p. 665 - 670
(2007/10/02)
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