Norcryptotackieine or 6H-indolo [2,3-b]quinoline is an indoloquinoline class of alkaloid isolated from Cryptolepis sanguinolenta that is traditionally used for antimalarial therapy. Additional structural tuning can extend the therapeutic potency of these indoloquinolines as antileishmanial drug leads. Synthesis of N-6-functionalized norcryptotackieines suffers from the necessity of complex pre-synthesized starting materials, restricted scope of functionalization, or tedious processes. Consequently, a straightforward synthetic procedure for accessing non-natural N-6-functionalized 6H-indolo[2,3-b]quinolines with potent antileishmanial activities is highly sought-after. Herein, we report a two-step one-pot synthesis of N-6-functionalized norcryptotackieine through a Pd-catalyzed double annulation reaction of commercially available amphipathic amines, 2-iodobenzyl cyanide, and differently functionalized 2-bromobenzaldehydes. The reported procedure allows a broad flexibility of substitution at the N-6 position and access to diversified scaffolds, including two natural products norcryptotackieine and neocryptolepine. Interestingly, 6d showed potent antileishmanial activities by causing disruption in the cytoskeletal structure and apoptotic-mediated death of parasites. Together, our work manifests the shortest route to N-6-substituted norcryptotackieine-derived antileishmanial agents.
Targeting the bend architecture: base de-stacking of the bend right-angled architecture of subdomain IIa leads to translational inhibition by a quinoxaline small molecule.
Norcryptotackieine (1a) belongs to the indoloquinoline
class of alkaloids isolated from Cryptolepis sanguinolenta, a plant species that has been traditionally used as an antimalarial
agent. Additional structural modifications of 1a can
potentially enhance its therapeutic potency. Indoloquinolines such
as cryptolepine, neocryptolepine, isocryptolepine, and neoisocryptolepine
show restricted clinical applications owing to their cytotoxicity
deriving from interactions with DNA. Here, we examined the effect
of substitutions at the N-6 position of norcryptotackieine on the
cytotoxicity, as well as structure–activity relationship studies
pertaining to sequence specific DNA-binding affinities. The representative
compound 6d binds DNA in a nonintercalative/pseudointercalative
fashion, in addition to nonspecific stacking on DNA, in a sequence
selective manner. The DNA-binding studies clearly establish the mechanism
of DNA binding by N-6-substituted norcryptotackieines and neocryptolepine.
The synthesized norcryptotackieines 6c,d and known indoloquinolines were screened on different cell lines
(HEK293, OVCAR3, SKOV3, B16F10, and HeLa) to assess their cytotoxicity.
Norcryptotackieine 6d (IC50 value of 3.1 μM)
showed 2-fold less potency when compared to the natural indoloquinoline
cryptolepine 1c (IC50 value of 1.64 μM)
in OVCAR3 (ovarian adenocarcinoma) cell lines.
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