Controlling the radical 5-exo-trig cyclization, and selective synthesis of seco-iso-cyclopropylfurano[e]indoline (seco-iso-CFI) and seco-cyclopropylthiophene[e]indoline (seco-CTI) DNA alkylating subunit of the duocarmycins

HxTfA 4 is a fluorescent analog of a potent cytotoxic and antimalarial agent, TfA 3, which is currently being investigated for the development of an antimalarial vaccine, PlasProtect®. HxTfA contains a p-anisylbenzimidazole or Hx moiety, which is endowed with a blue emission upon excitation at 318 nm; thus enabling it to be used as a surrogate for probing the cellular fate of TfA using confocal microscopy, and addressing the question of nuclear localization. HxTfA exhibits similar selectivity to TfA for A-tract sequences of DNA, alkylating adenine-N3, albeit at 10-fold higher concentrations. It also possesses in vitro cytotoxicity against A549 human lung carcinoma cells and Plasmodium falciparum. Confocal microscopy studies showed for the first time that HxTfA, and by inference TfA, entered A549 cells and localized in the nucleus to exert its biological activity. At biologically relevant concentrations, HxTfA elicits DNA damage response as evidenced by a marked increase in the levels of γH2AX observed by confocal microscopy and immunoblotting studies, and ultimately induces apoptosis.

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Synthetic approaches, functionalization and therapeutic potential of quinazoline and quinazolinone skeletons: The advances continue

Khan

Ibrar

Ahmed

et al. 2015

European Journal of Medicinal Chemistry

360

131

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Controlling the radical 5-exo-trig cyclization, and selective synthesis of seco-iso-cyclopropylfurano[e]indoline (seco-iso-CFI) and seco-cyclopropylthiophene[e]indoline (seco-CTI) DNA alkylating subunit of the duocarmycins

Cited by 5 publications

References 22 publications

Synthesis and evaluation of duocarmycin SA analogs incorporating the methyl 1,2,8,8a-tetrahydrocyclopropa[c]imidazolo[4,5-e]indol-4-one-6-carboxylate (CImI) alkylation subunit

Synthesis and evaluation of duocarmycin SA analogs incorporating the methyl 1,2,8,8a-tetrahydrocyclopropa[c]imidazolo[4,5-e]indol-4-one-6-carboxylate (CImI) alkylation subunit

Design, synthesis, nuclear localization, and biological activity of a fluorescent duocarmycin analog, HxTfA

Synthetic approaches, functionalization and therapeutic potential of quinazoline and quinazolinone skeletons: The advances continue

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