Tetrahydroquinoline units in flexible heteroarotinoids (Flex-Hets) convey anti-cancer properties in A2780 ovarian cancer cells

Gnanasekaran, Krishna Kumar; Pouland, Tim; Bunce, Richard A.; Berlin, K. Darrell; Abuskhuna, Suaad; Bhandari, Dipendra; Mashayekhi, Maryam; Zhou, Donghua H.; Benbrook, Doris M.

doi:10.1016/j.bmc.2019.115244

Cited by 5 publications

(2 citation statements)

References 39 publications

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“…Cyclization of α-trialkyl-ATAs 10a , b (derived from 2-bromostyrene) was accomplished using a palladium-mediated intramolecular Buchwald–Hartwig C–N bond formation, affording 1,2,3,4-tetrahydroquinolines (THQs) 11a , b displaying the α-trialkyl-ATA motif embedded within its framework. The generic THQ-pharmacophore is well-established in a variety of contexts in medicinal chemistry, however, those displaying an α-trialkyl-ATA motif are scarce and so expedient access to new derivatives is desirable …”

Section: Resultsmentioning

confidence: 99%

Modular Photocatalytic Synthesis of α-Trialkyl-α-Tertiary Amines

et al. 2021

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Molecules displaying an α-trialkyl-α-tertiary amine motif provide access to an important and versatile area of biologically relevant chemical space but are challenging to access through existing synthetic methods. Here, we report an operationally straightforward, multicomponent protocol for the synthesis of a range of functionally and structurally diverse α-trialkyl-α-tertiary amines, which makes use of three readily available components: dialkyl ketones, benzylamines, and alkenes. The strategy relies on the of use visible-light-mediated photocatalysis with readily available Ir(III) complexes to bring about single-electron reduction of an all-alkyl ketimine species to an α-amino radical intermediate; the α-amino radical undergoes Giese-type addition with a variety of alkenes to forge the α-trialkyl-α-tertiary amine center. The mechanism of this process is believed to proceed through an overall redox neutral pathway that involves photocatalytic redox-relay of the imine, generated from the starting amine-ketone condensation, through to an imine-derived product. This is possible because the presence of a benzylic amine component in the intermediate scaffold drives a 1,5-hydrogen atom transfer step after the Giese addition to form a stable benzylic α-amino radical, which is able to close the photocatalytic cycle. These studies detail the evolution of the reaction platform, an extensive investigation of the substrate scope, and preliminary investigation of some of the mechanistic features of this distinct photocatalytic process. We believe this transformation will provide convenient access to previously unexplored α-trialkyl-α-tertiary amine scaffolds that should be of considerable interest to practitioners of synthetic and medicinal chemistry in academic and industrial institutions.

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Section: Resultsmentioning

confidence: 99%

Modular Photocatalytic Synthesis of α-Trialkyl-α-Tertiary Amines

et al. 2021

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“…In addition, values of log Po/w of 3.74 and 3.35 for 5a (R = CH 3 ) and 5b (R = OCH 3 ), respectively, indicate that these compounds are less hydrophobic than compounds 5c (R = Cl) and 5d (R = Br), for which log Po/w are 3.97 and 4.10, respectively. In the literature, several authors have suggested that reduced hydrophobicity can be associated with the efficiency of cytotoxicity, as this property is directly related to the binding to cellular targets [54,55]. Besides, retrovirus infection alters lipid synthesis, leading to an alteration in the cell membrane [56].…”

Section: Biological Activitymentioning

confidence: 99%

Synthetic (E)-3-Phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium Chloride Derivatives as Promising Chemotherapy Agents on Cell Lines Infected with HTLV-1

et al. 2020

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Synthesis of four compounds belonging to mesoionic class, (E)-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives (5a–d) and their biological evaluation against MT2 and C92 cell lines infected with human T-cell lymphotropic virus type-1 (HTLV-1), which causes adult T-cell leukemia/lymphoma (ATLL), and non-infected cell lines (Jurkat) are reported. The compounds were obtained by convergent synthesis under microwave irradiation and the cytotoxicity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Results showed IC50 values of all compounds in the range of 1.51–7.70 μM in HTLV-1-infected and non-infected cells. Furthermore, it was observed that 5b could induce necrosis after 24 h for Jurkat and MT2 cell lines. The experimental (fluorimetric method) and theoretical (molecular docking) results suggested that the mechanism of action for 5b could be related to its capacity to intercalate into DNA. Moreover, the preliminary pharmacokinetic profile of the studied compounds (5a–d) was obtained through human serum albumin (HSA) binding affinity using multiple spectroscopic techniques (circular dichroism, steady-state and time-resolved fluorescence), zeta potential and molecular docking calculations. The interaction HSA:5a–d is spontaneous and moderate (Ka ~ 104 M−1) via a ground-state association, without significantly perturbing both the secondary and surface structures of the albumin in the subdomain IIA (site I), indicating feasible biodistribution in the human bloodstream.

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