Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects

Kim, Jin Han; Jeong, Hui Rak; Jung, Da Woon; Yoon, Hong Bin; Kim, Sun Young; Kim, Hyoung Ja; Lee, Kyung‐Tae; Gadotti, Vinícius M.; Huang, Junting; Zhang, Fang-Xiong; Zamponi, Gerald W.; Lee, Jae Yeol

doi:10.1016/j.bmc.2017.07.010

Cited by 8 publications

(4 citation statements)

References 39 publications

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“…Despite scarcity, data available for other blockers including dihydroquinazolines, diphenylbutylpiperidines, diphenylpiperazines and succinimides are also indicative of a hyperpolarizing shift of inactivation. Additionally, an increased slope factor for inactivation could be seen for -methyl-phenylsuccinimide on Ca v 3.1 and Ca v 3.2 channels in [109] and for KYS05090S [70], KCP10060F and KCP10067F [73] DHQ on Ca v 3.2 channels, although these data were not quantified.…”

Section: Box 1 How Channel Availability Depends On Steady-state Inactivation Parametersmentioning

confidence: 98%

The Hard-To-Close Window of T-Type Calcium Channels

Visa

Shaikh

Alza

et al. 2019

Trends in Molecular Medicine

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Section: Box 1 How Channel Availability Depends On Steady-state Inactivation Parametersmentioning

confidence: 98%

The Hard-To-Close Window of T-Type Calcium Channels

Visa

Shaikh

Alza

et al. 2019

Trends in Molecular Medicine

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Section: Introductionmentioning

confidence: 99%

“…The chemistry of 3,4-dihydroquinazolines and 4 H -3,1-benzothiazines is of constant interest owing to the occurrence of these ring systems in various biologically important compounds ( Figure 1 ). A number of 3,4-dihydroquinazolines were found to show remarkable anticancer [ 1 ], antiviral [ 2 ], antidepressant [ 3 ], antifungal [ 4 ], selective somatostatin 2 (ss2) agonistical [ 5 ], β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitive [ 6 ], and cholinesterase enzyme inhibitive activities [ 7 ]. The 3,4-dihydroquinazoline skeleton also exists in some natural products such as vasicine and vasicoline [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

New efficient synthesis of polysubstituted 3,4-dihydroquinazolines and 4H-3,1-benzothiazines through a Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution sequence

Zhao¹,

Yang²,

Liu³

et al. 2022

Beilstein J. Org. Chem.

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A new efficient synthesis of polysubstituted 3,4-dihydroquinazolines and 4H-3,1-benzothiazines via sequential Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution reaction has been developed. The three-component Passerini reactions of 2-azidobenzaldehydes 1, benzoic acid (2), and isocyanides 3 produced the azide intermediates 4, which were treated sequentially with triphenylphosphine, isocyanates (or CS2), and secondary amines to give polysubstituted 3,4-dihydroquinazolines 8 and 4H-3,1-benzothiazines 11 in good overall yields through consecutive Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution reactions.

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“…In our previous work, a family of 3,4-dihydroquinazoline derivatives was discovered as a promising anticancer agent [8][9][10], among which KCP-10043F (OZ-001) represses the proliferation of human A549 lung cancer cells by caspasemediated apoptosis via STAT3 inactivation [11,12]. is compound was a racemate (±)-3,4-dihydroquinazoline derivative with a single chiral center (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent

Ahn

Yang

et al. 2021

Journal of Chemistry

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If a new drug candidate will be a mixture of enantiomers, both enantiomers should be separately studied for at least latent genotoxicity as early as possible since the thalidomide tragedy. Our group has recently reported that KCP-10043F (OZ-001) as a racemate (±)-3,4-dihydroquinazoline derivative strongly represses the proliferation of human A549 lung cancer cells by caspase-mediated apoptosis via STAT3 inactivation. To investigate the possible teratological effects of the two enantiomers of a racemic KCP-10043F, therefore chiral resolution of (±)-KCP-10043F was performed and subsequently followed by a series of chemical processes to afford the corresponding chiral diastereomers. By using 1H NMR anisotropy method, the absolute configuration (+)-KCP-10043F and (−)-KCP-10043F could be assigned as S and R configuration, respectively. The bacterial reverse mutation test (Ames test) for racemate (±)-KCP-10043F and its two enantiomers exhibited that all three stereoisomers were found to be nongenotoxic against five bacterial strains with/without metabolic activation. In addition, (R)-(−)-KCP-10043F displayed almost equal anticancer activity to (S)-(+)-KCP-10043F against three cancer cell lines. Based on these overall results, racemate KCP-10043F (OZ-001) could be used for our ongoing preclinical and clinical studies without the expensive asymmetric process and/or chiral separation.

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Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects

Cited by 8 publications

References 39 publications

The Hard-To-Close Window of T-Type Calcium Channels

The Hard-To-Close Window of T-Type Calcium Channels

New efficient synthesis of polysubstituted 3,4-dihydroquinazolines and 4H-3,1-benzothiazines through a Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution sequence

Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent

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