Antitumor studies. Part 4: Design, synthesis, antitumor activity, and molecular docking study of novel 2-substituted 2-deoxoflavin-5-oxides, 2-deoxoalloxazine-5-oxides, and their 5-deaza analogs

Various novel 10-alkyl-2-deoxo-2-methylthioflavin-5-oxides and their 2-alkylamino derivatives were prepared by facile nitrosative cyclization of 6-(N-alkylanilino)-2-methylthiopyrimidin-4(3H)-ones followed by nucleophilic replacement of the 2-methylthio moiety by different amines, and acidic hydrolysis of the 2-methylthio moiety afforded the corresponding flavin derivatives. 2-Deoxo-2-methylthio-5-deazaalloxazines and 2-deoxo-2-methylthioalloxazine-5-oxides were also prepared by Vilsmeier reaction and by nitrosation of 6-anilino-2-methylthiopyrimidin-4(3H)-ones, respectively. Then, they were subjected to nucleophilic replacement with appropriate amines to produce the corresponding 2-alkylamino derivatives. Regiospecific N-3-alkylation of 2-deoxo-2-methylthioalloxazine-5-oxides was carried out with various alkylating agents in the usual way, The antitumor activities against CCRF-HSB-2 and KB tumor cells have been investigated in vitro, and many compounds showed promising antitumor activities. Furthermore, AutoDock molecular docking into PTK (PDB: 1t46) has been done for lead optimization of the aforementioned compounds as potential PTK inhibitors

An Initial Case Report of a Laparoscopic Spleen-Preserving Distal Pancreatectomy for a Patent with a Pancreatic Metastasis of Malignant Melanoma

Article信州医学雑誌 63(1):19-24(2015)journal articl

Synthesis and regioselective N- and O-alkylation of 3-alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones and 2-phenyl-9-propyl-9H-purin-6(1H)-one with evaluation of antiviral and antitumor activities

3-Alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones were prepared by nitrosative cyclization of the appropriate 5,6-diamino-2-phenylpyrimidin-4(3H)-ones with nitrous acid and were subjected to regioselective alkylation with several alkylating agents in aprotic solvent at different temperature. Simultaneous 6-N- and 7-O-alkylation were observed and the regioselectivity varied remarkably with size and shape of the alkylating agents as well as with the reaction temperature. Similarly, N- and O-alkylation as well as selectivity was also observed in the case of 2-phenyl-9-propyl-9H-purin-6(1H)-one. Some of the synthesized compounds showed moderate antiviral and antitumor activities.</p

Antitumor studies. Part 1: Design, synthesis, antitumor activity, and AutoDock study of 2-deoxo-2-phenyl-5-deazaflavins and 2-deoxo-2-phenylflavin-5-oxides as a new class of antitumor agents

Novel 2-deoxo-2-phenyl-5-deazaflavins and 2-deoxo-2-phenylflavin-5-oxides were prepared as a new class of antitumor agents and showed significant antitumor activities against NCI-H 460, HCT 116, A 431, CCRF-HSB-2, and KB cell lines. In vivo investigation, 2-deoxo-10-methyl-2-phenyl-5-deazaflavin exhibited the effective antitumor activity against A 431 human adenocarcinoma cells transplanted subcutaneously into nude mouse. Furthermore, AutoDock study has been done by binding of the flavin analogs into PTK pp60(c-src), where a good correlation between their IC50 and AutoDock binding free energy was exhibited. In particular, 2-deoxo-2-phenylflavin-5-oxides exhibited the highest potential binding affinity within the binding pocket of PTK

Antitumor studies. Part 3: Design, synthesis, antitumor activity, and molecular docking study of novel 2-methylthio-, 2-amino-, and 2-(N-substituted amino)-10-alkyl-2-deoxo-5-deazaflavins

Various novel 10-alkyl-2-deoxo-2-methylthio-5-deazaflavins have been synthesized by reaction of 6-(N-alkylanilino)-2-methylthiopyrimidin-4(3H)-ones with Vilsmeier reagent. The similar 2-(N-substituted amino) derivatives were prepared by nucleophilic replacement reaction of the 2-methylthio moiety by appropriate amines. The 2-oxo derivatives (i.e., 5-deazaflavins) were obtained by acidic hydrolysis of the 2-methylthio derivatives. The antitumor activities against CCRF-HSB-2 and KB cells and the antiviral activities against HSV-1 and HSV-2 have been investigated in vitro, and many compounds showed promising antitumor activities. Furthermore, AutoDock molecular docking into PTK has been done for lead optimization of these compounds as potential PTK inhibitors. Whereas, the designed 2-deoxo-5-deazaflavins connected with amino acids at the 2-position exhibited the good binding affinities into PTK with more hydrogen bonds

Inhibition Mechanism of EFdA, a Highly Potent Inhibitor of HIV Reverse Transcriptase [abstract]

Comparative Medicine - OneHealth and Comparative Medicine Poster SessionThe nucleoside 4'-ethynyl-2-fluoro-deoxyadenosine (EFdA) is one of the most potent antiretroviral nucleosides yet described, inhibiting replication of wild-type and multidrug-resistant HIV-1 strains in vitro (PBMC cells) with an EC50 as low as 50 pM. Our laboratory works in collaboration with academic, government and pharmaceutical industry laboratories, to characterize the mechanism of action of EFdA, and help develop it as a therapeutic for the treatment of HIV-infected patients, and as a topical microbicide to minimize sexual transmission of HIV. We have recently shown that the potency of antiviral activity stems in part from a mechanism of action not shown by any of the clinically used nucleoside antiretrovirals. Unlike other Reverse Transcriptase (RT) inhibitors, EFdA has a 3'-OH group which is necessary for nucleotide incorporation, yet it acts as a chain-terminator of retroviral DNA synthesis. Using biochemical techniques, we have determined that EFdA is incorporated very efficiently into the nascant viral DNA chain and blocks the incorporation of incoming nucleotides by stopping the translocation/movement of RT. Therefore, we have dubbed EFdA as a Translocation-Defective RT Inhibitor (TDRTI). A pilot collaborative study spearheaded by collaborators Parniak and Corb demonstrated that EFdA treatment of Rhesus Macaques resulted in a 2-3 log decrease in simian immunodeficiency virus (SIV) within seven days; these levels declined to undetectable levels (5-log reduction) within 2 months and essentially remained so for the duration of therapy. Hence, EFdA is a highly potent HIV RT inhibitor with in vitro and in vivo antiviral activities that warrant further development of the compound as a potential therapeutic for individuals harboring wild-type and/or multi-drug resistant HIV-1