Search

This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 (BRCA1/2) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.

To discover new acetyl-CoA carboxylase (ACCase) inhibiting-based herbicides, twenty-nine novel quinazolin-4(3H)-one derivatives were designed and synthesized based on the aryloxyphenoxypropionate motif. The bioassay results showed that most of the target compounds showed better pre-emergent herbicidal activity against monocotyledonous weeds in a greenhouse. Especially, when applied at 375 g ha−1 under pre-emergence conditions, compound QPP-7 displayed excellent herbicidal activity against monocotyledonous weeds (i.e., E. crusgalli, D. sanguinalis, P. alopecuroides, S. viridis, E. indica, A. fatua, E. dahuricu, S. alterniflora) with inhibition rate >90%, and displayed excellent crop safety to O. sativa, T. aestivum, G. spp, and A. hypogaea. The study of structure-activity relationship (SAR) revealed that the herbicidal activity of target compounds is strongly influenced by the spatial position of R group and the bulk of R1 group on quinazolin-4(3H)-one, and the (R = 6-F, R1 = Me) pattern is confirmed as the optimal orientation. Furthermore, the molecular docking study and the good inhibitory activity of QPP-7 against E. crusgalli ACCase enzyme (IC50 = 54.65 nM) indicated that it may be a ACCase inhibitor. Taken together, the present work demonstrated that compound QPP-7 could serve as a potential lead structure for further developing novel ACCase inhibiting-based herbicide.

This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 (BRCA1/2) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer. The first potential BRD4 and PARP1 inhibitors 19d named ADTL-BPI1901 was discovered and synthesized by fragment-based combinatorial screening and activity assays led to the three rounds of structural optimization. Preliminary structure−activity relationships, molecular modeling, pharmacokinetics and favorable in vivo antitumor efficacy of 19d were investigated. Image 1 [ABSTRACT FROM AUTHOR]

An efficient, eco-friendly synthesis of a series of 2-{[3-oxo-3-(alkyl/aryl-1-yl)alkyl]thio}-3-substituted quinazolin-4(3H)-ones employing quinazolin-4(3H)-one and corresponding halo-acyl/haloalkyl as electrophiles is presented. The products were assayed for anti-bacterial activity on four bacterial species (Pseudomonas aeruginosa, Escherichia coli, Bacillus subtilis, and Staphylococcus aureus). In-silico molecular docking studies were carried out. [ABSTRACT FROM AUTHOR]

[Display omitted] • Three series of novel 6-(imidazo[1,2-a] pyridin-6-yl)-quinazolin-4(3H)-one derivatives were designed and synthesized. • Compound 12d exhibited potent anti-tumor activity in vitro and in vivo. • Compound 12d induced mitotic catastrophe and cell apoptosis in SH-SY5Y cells. • Compound 12d was identified as a novel dual ROR1/Aurora kinase inhibitor. ROR1 and Aurora kinase were overexpressed in various cancers and essential for cell proliferation, survive and metastasis. Pharmaceutical inhibition of ROR1 and Aurora kinase abrogated the activation of downstream signaling and induced cancer cell apoptosis. Hence, ROR1 and Aurora kinase considered as attractive therapeutic targets for the development of anticancer drugs. In the present work, three series of novel 6-(imidazo[1,2- a ] pyridin-6-yl)-quinazolin-4(3 H)-one derivatives were designed and synthesized via bioisosterism and scaffold-hopping strategies guided by FLF-13, an Aurora kinase inhibitor we discovered earlier. Most of compounds in series 2 and series 3 showed submicromolar to nanomolar inhibitory activity against multiple cancer cell lines. More importantly, compounds 12d and 12f in series 3 showed nanomolar inhibitory activity against all test cancer cells. The most promising compound 12d exhibited potent inhibitory activity against Aurora A and Aurora B with IC 50 values of 84.41 nM and 14.09 nM, respectively. Accordingly, compounds 12d induced G2/M phase cell cycle arrest at 24 h and polyploidy at 48 h. It's worth noting that 12d also displayed inhibitory activity against ROR1 and induce cell apoptosis. Furthermore, 12d could significantly inhibit the tumor growth in SH-SY5Y xenograft model with tumor growth inhibitory rate (IR) up to 46.31 % at 10 mg/kg and 52.66 % at 20 mg/kg. Overall, our data suggested that 12d might serve as a promising candidate for the development of therapeutic agents for cancers with aberrant expression of ROR1 and Aurora kinases by simultaneously targeting ROR1 and Aurora kinase. [ABSTRACT FROM AUTHOR]

Highlights: [•] (α-Fe2O3)-MCM-41-l-prolinium nitrate is a new magnetically recoverable nanocatalyst. [•] Combination of ionic liquid and magnetic mesoporous silica as reaction medium and catalyst without using extra organic solvents. [•] Chemoselective formation of aromatic quinazolinone product instead dihydroquinazolinone. [Copyright &y& Elsevier]

This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 ( BRCA1/2 ) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Background: Compounds containing the quinazoline-4(3H)-one framework constitute an important class of fused N-heterocycles that are found in more than 200 naturally occurring alkaloids. These compounds also show a diverse range of pharmacological activities including antitumor properties. This prompted us to explore a series of quinazolin-4-(3H)-one derivatives having no substituent at C-2 as potential cytotoxic agents., Objective: The objective of this study was to synthesize and evaluate 3-substituted quinazolin-4(3H)-one derivatives for their potential cytotoxic properties., Methods: A convenient method has been developed for the rapid synthesis of this class of compounds under a mild and non-hazardous reaction condition in good yields. The methodology involved a three-component reaction employing isatoic anhydride, amines and glyoxylic acid as reactants in the presence of lemon juice in PEG- 400 at room temperature (25-30ºC) under ultrasound irradiation. All the synthesized compounds were screened via an MTT assay for their potential cytotoxic properties in vitro using the cancerous cell lines e.g. A549, A2780, HepG2, K562, MCF-7 and HCT-116 and a non-cancerous HEK293 cell line., Results: Several compounds such as 3a, 3b, 3d, 3e and 3f showed promising growth inhibition against these cancer cell lines but no significant effects on HEK293 cell line. The IC50 values of these compounds were comparable to doxorubicin whereas 3f significantly induced apoptosis in MCF-7 cells that also was comparable to doxorubicin., Conclusion: An ultrasound-assisted MCR facilitated by lemon juice has been developed to synthesize 3- substituted quinazolin-4(3H)-one derivatives that could act as potential anticancer agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)