Search for inhibitors of bacterial and human protein kinases among derivatives of diazepines[1,4] annelated with maleimide and indole cycles.
Aminomethylation of 9b,10-dihydro-1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino-[1,7-a]indole-1,3(2H)-diones or 1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino[1,7-a]indole-1,3(2H)-diones resulted in dialkylaminomethyl derivatives. Alkylation of the nitrogen atom of maleimide moiety of polyannelated diazepines with 1,3-dibromopropane and subsequent reaction with thiourea or its N-alkyl derivatives gave isothiourea-carrying compounds. The compounds containing isothiourea moiety were active against individual human serine/threonine and tyrosine kinases at low micromolar concentrations. Dialkylaminomethyl derivatives of diazepines sensitized Streptomyces lividans with overexpressed aminoglycoside phosphotransferase type VIII (aphVIII) to kanamycin by inhibiting serine/threonine kinase(s) mediated aphVIII phosphorylation.
Danilenko
Valery N
VN
Vavilov Institute of General Genetics, 3 Gubkin Street, Moscow 119991, Russia.
Simonov
Alexander Y
AY
Lakatosh
Sergey A
SA
Kubbutat
Michael H G
MH
Totzke
Frank
F
Schächtele
Christoph
C
Elizarov
Sergey M
SM
Bekker
Olga B
OB
Printsevskaya
Svetlana S
SS
Luzikov
Yuryi N
YN
Reznikova
Marina I
MI
Shtil
Alexander A
AA
Preobrazhenskaya
Maria N
MN
D002626:Chemistry, Pharmaceutical / Q000379:methods; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008301:Maleimides / Q000737:chemistry*; D008956:Models, Chemical; D008968:Molecular Conformation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D012694:Serine / Q000737:chemistry; D048170:Streptomyces lividans / Q000378:metabolism; D013890:Thiourea / Q000737:chemistry; D013912:Threonine / Q000737:chemistry
D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; C043592:maleimide; D013912:Threonine; D012694:Serine; D011494:Protein Kinases; D013890:Thiourea