One-Pot Cascade Annulation-Triggered Synthesis of N-6-Substituted Norcryptotackieine Alkaloids and Evaluation of Their Antileishmanial Activities

Abstract

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.

Sequence-Specific Dual DNA Binding Modes and Cytotoxicities of N-6-Functionalized Norcryptotackieine Alkaloids

“…Our aim was to bring about N-6 functionalization of norcryptotackieines with the purpose of inducing suitable DNA interactions and modulation of their cytotoxic properties. Further, N-6-substituted norcryptotackieines can easily be synthesized using a Pd-catalyzed double annulation reaction of amines, 2-iodobenzyl cyanide, and 2-bromobenzaldehydes . Condensation of commercially available 2-iodobenzyl cyanide 2 and 2-bromobenzaldehyde 3 with K 2 CO 3 in anhydrous MeOH at rt delivered the ( E )-stilbene intermediate 4 .…”

“…(Z)-3-(2-Bromophenyl)-2-(2-iodophenyl)acrylonitrile (4). 5 1 H NMR (400 MHz, CDCl 3 ) δ 7.10−7.14 (m, 1H), 7.29−7.33 (m, 1H), 7.42−7.49 (m, 4H), 7.65−7.68 (m, 1H), 7.96 (d, J = 7.9 Hz, 1H), 8.12 (dd, J = 7.8, 1.5 Hz, 1H); 13 General Procedure for Synthesis of N-6-Substituted Norcryptotackieine 6. To a mixture of substrate 4 (0.5 g, 1.2 mmol) in dry toluene (15 mL) were added Pd 2 (dba) 3 (0.11 g, 0.12 mmol), xantphos (0.21 g, 0.36 mmol), and NaO t Bu (0.46 g, 4.8 mmol) at rt.…”

“…Recently we reported a Pd-catalyzed one-pot two-step synthesis of a pool of N-6-functionalized norcryptotackieines 6 with a broad flexibility of substitution. Some of these synthetic derivatives showed potential antileishmanial activity by promoting morphological alterations and causing apoptotic-mediated death of parasites …”

“…Some of these synthetic derivatives showed potential antileishmanial activity by promoting morphological alterations and causing apoptoticmediated death of parasites. 5 Despite potential pharmacological properties, this class of alkaloids is not extensively used clinically, primarily due to toxic side effects presumably arising from their DNA binding ability. 6 Among fused indoloquinoline systems, the DNAbinding mode has been deciphered from the crystal structure for 1c, where it intercalates at CC sites in d(CCTAGG) 2 with the two ring nitrogen atoms, facing the opposite sides, snugly fit between two pairs of oxygen atoms originating from sequence contiguous guanine and cytosine rings.…”

“…Further, N-6-substituted norcryptotackieines can easily be synthesized using a Pd-catalyzed double annulation reaction of amines, 2-iodobenzyl cyanide, and 2bromobenzaldehydes. 5 Condensation of commercially available 2-iodobenzyl cyanide 2 and 2-bromobenzaldehyde 3 with K 2 CO 3 in anhydrous MeOH at rt delivered the (E)-stilbene intermediate 4. Sequential Pd 2 (dba) 3 -catalyzed intermolecular and intramolecular double Buchwald−Hartwig C−N coupling with differently functionalized aliphatic and aromatic amines 5 in toluene at 110 °C yielded the desired products 6a−j and 6n in moderate to good yields (Scheme 1A).…”