Quinazoline Derivative kzl052 Suppresses Prostate Cancer by Targeting WRN Helicase to Stabilize DNA Replication Forks.

WRN helicases play a key role in DNA replication, repair, and other processes in a variety of tumors. It has become one of the hot targets of genotoxic drugs, but the effect and mechanism of targeting WRN against prostate cancer is still unclear. In our previous study, we found a quinazoline compound kzl052, which has a WRN-dependent inhibitory effect on prostate cancer cells, but its molecular mechanism needs to be further explored.

Design and synthesis of 2-amino-4-(trifluoromethyl)pyrimidine derivatives as potential Werner-dependent antiproliferative agents.

To uncover novel inhibitors of Werner (WRN) helicase, this study adopted the scaffold-hopping strategy to design and synthesize 24 novel 2-amino-4-(trifluoromethyl)pyrimidine derivatives. The MTT assay was employed to evaluate the anticancer activity of target compounds against microsatellite instability-high (MSI-H) cell lines (HCT116 and LNCaP) and microsatellite stability (MSS) cell lines (SW620 and PC3). Some compounds demonstrated significant inhibitory activity against all four cancer cell lines.

Discovery of novel quinazoline derivatives containing trifluoromethyl against cell proliferation by targeting werner helicase.

A series of novel 2-trifluoromethyl-4-aminoquinazoline derivatives were designed and synthesized, and their antitumor activities were evaluated. Among them, several target compounds exhibited nanomolar inhibitory activities against K562 and LNCaP. Meanwhile, the results of in vitro and in vivo activity evaluation showed that compound 9 had the significant selective anticancer activity and the lower toxicity.

Hit to lead optimization of the 4-trifluoromethylquinoline derivatives as novel SGK1 inhibitors with potent anti-prostate cancer activity.

Prostate cancer (PCa) remains a significant health concern for males, and serum/glucocorticoid-regulated kinase-1 (SGK1) plays a crucial role in its pathogenesis. This provides a promising target for the development of novel therapies against PCa. Herein, we reported the structural optimization of the hit compound H1, which was discovered in our previous work as an SGK1 inhibitor.

Design, Synthesis, and Biological Evaluation of Novel Trifluoromethylated Dipeptide Mimetics of Matijin-Su as Potent Anti-HBV Agents.

A series of Matijin-Su (MTS) derivatives were designed, synthesized and their anti-hepatitis B virus (HBV) activities were evaluated in vitro. Twelve compounds displayed good inhibitory activity against HBV DNA replication with IC values at micromolar level (0.14-4.

MMP13 as an effective target of an active trifluoromethyl quinazoline compound against osteosarcoma.

Osteosarcoma (OS) is a highly fatal malignant tumor with a high metastatic rate and poor prognosis. Matrix metalloproteinase-13 (MMP13) is involved in OS metastasis. Its increased expression is closely related to distant metastasis and poor prognosis.

Quinazoline derivatives inhibit cell growth of prostate cancer as a WRN helicase dependent manner by regulating DNA damage repair and microsatellite instability.

WRN helicase is a crucial target of synthetic death in cancer and has a unique advantage in the treatment of microsatellite unstable cancers. Our previous studies have found that quinazoline derivatives showed the WRN-dependent antiproliferative activity. In this study, a series of new quinazoline derivatives were designed and synthesized by optimizing the structure, and evaluating the targeting and sensitivity to WRN helicase.

Discovery of novel 4-trifluoromethyl-2-anilinoquinoline derivatives as potential anti-cancer agents targeting SGK1.

Given the critical necessity for the development of more potent anti-cancer drugs, a series of novel compounds incorporating trifluoromethyl groups within the privileged 2-anilinoquinoline scaffold was designed, synthesized, and subjected to biological evaluation through a pharmacophore hybridization strategy. Upon evaluating the in vitro anti-cancer characteristics of the target compounds, it became clear that compound 8b, which contains a (4-(piperazin-1-yl)phenyl)amino substitution at the 2-position of the quinoline skeleton, displayed superior efficacy against four cancer cell lines by inducing apoptosis and cell cycle arrest. Following research conducted in a PC3 xenograft mouse model, it was found that compound 8b exhibited significant anti-cancer efficacy while demonstrating minimal toxicity.

Design and synthesis of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives as potential Werner-dependent antiproliferative agents.

To discover new Werner (WRN) helicase inhibitors, a series of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives were designed and synthesized through a structural optimization strategy, and the anticancer activities of 25 new target compounds against PC3, K562, and HeLa cell lines were evaluated by the MTT assay. Some of these compounds exhibited excellent inhibitory activity against three different cancer cell lines. Compounds 6a, 8i, and 13a showed better antiproliferative activity against K562 cells, with IC values of 3871.

Design, Synthesis, and Biological Evaluation of Novel Quinazoline Derivatives Possessing a Trifluoromethyl Moiety as Potential Antitumor Agents.

A novel series of trifluoromethyl-containing quinazoline derivatives with a variety of functional groups was designed, synthesized, and tested for their antitumor activity by following a pharmacophore hybridization strategy. Most of the 20 compounds displayed moderate to excellent antiproliferative activity against five different cell lines (PC3, LNCaP, K562, HeLa, and A549). After three rounds of screening and structural optimization, compound 10 b was identified as the most potent one, with IC values of 3.

Design, synthesis and antitumor activity of 2-substituted quinazoline-4-amine derivatives.

Werner (WRN) syndrome protein is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers. In this study, a series of new N-arylquinazoline-4-amine analogs were designed and synthesized based on structure optimization of quinazoline.

Trifluoromethyl quinoline derivative targets inhibiting HDAC1 for promoting the acetylation of histone in cervical cancer cells.

Cervical cancer is the leading cause of death among gynecological malignant tumors, especially due to the poor prognosis of patients with advanced tumors due to recurrence, metastasis, and chemotherapy resistance. Therefore, exploring new antineoplastic drugs with high efficacy and low toxicity may bring new expectations in patients with cervical cancer. Natural products and their derivatives exert an antitumor activity.

Design, synthesis and bioevaluation of novel prenylated chalcones derivatives as potential antitumor agents.

A series of novel prenylated chalcone derivatives with broad spectrum anticancer potential were designed and synthesized. Some of the synthesized target compounds showed potent anti-proliferative activities toward LNCaP (prostate cancer cell line), K562 (human leukemia cells), A549 (human lung carcinoma cell line) and HeLa (cervical cancer cell line) cell lines. Among of the active compounds, (E)-1-(4-(2-(diethylamino)ethoxy)-2-hydroxy-6-methoxy-3-(3-methylbut-2-en-1-yl)phenyl)-3-(pyridin-3-yl)prop-2-en-1-one (C36) was directly interacted with protein kinase B (PKB), also known as AKT, significantly inhibited the pPI3K, pAKT(Ser473) protein levels to repress the growth of cancer cells by inducing apoptosis, arresting cell cycle.

A Novel Quinazoline Derivative Prevents and Treats Arsenic-Induced Liver Injury by Regulating the Expression of RecQ Family Helicase.

Arsenic is a carcinogenic metalloid toxicant widely found in the natural environment. Acute or prolonged exposure to arsenic causes a series of damages to the organs, mainly the liver, such as hepatomegaly, liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Therefore, it is imperative to seek drugs to prevent arsenic-induced liver injury.

Design, synthesis and bioevaluation of novel trifluoromethylquinoline derivatives as tubulin polymerization inhibitors.

A series of novel trifluoromethylquinoline derivatives were designed, synthesized and evaluated for antitumor activities. All compounds were evaluated for antiproliferative activity against four human cancer cell lines. Among them, , , and exhibited remarkable antiproliferative activities against all the tested cell lines at nanomolar concentrations.

Discovery of novel 2-(trifluoromethyl)quinolin-4-amine derivatives as potent antitumor agents with microtubule polymerization inhibitory activity.

In this work, a series of 2-(trifluoromethyl)quinolin-4-amine derivatives were designed and synthesized through structural optimization strategy as a microtubule-targeted agents (MTAs) and their cytotoxicity activity against PC3, K562 and HeLa cell lines were evaluated. The half maximal inhibitory concentration (IC) of 5e, 5f, and 5o suggested that their potency of anti-proliferative activities against HeLa cell lines were better than the combretastatin A-4. Compound 5e showed the higher anti-proliferative activity against PC3, K562 and HeLa in vitro with IC values of 0.

Discovery of novel N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives as the inhibitors of tubulin polymerization in leukemia cells.

A series of new N-aryl-2-trifluoromethylquinazoline-4-amine analogs were designed and synthesized based on structure optimization of quinazoline by introducing a trifluoromethyl group into 2-position. The structures of the twenty-four newly synthesized compounds were confirmed by H NMR, C NMR and ESI-MS. The in vitro anti-cancer activity against chronic myeloid leukemia cells (K562), erythroleukemia cells (HEL), human prostate cancer cells (LNCaP), and cervical cancer cells (HeLa) of the target compounds was evaluated.

A novel L-phenylalanine dipeptide inhibits prostate cancer cell proliferation by targeting TNFSF9.

In the present study, a series of novel L-phenylalanine dipeptides were designed and synthesized by a multi-step sequence of reactions, including carbodiimide-mediated condensation, hydrolysis, mixed anhydride condensation, and nucleophilic substitution. Among them, compound 7c exhibited potent antitumor activity against prostate cancer cell PC3 in vitro and in vivo via inducing apoptosis. We investigated the significantly differentially expressed proteins in the cells caused by the compound 7c to unravel the molecular mechanisms underlying the regulation of PCa cell growth, which indicated that 7c mainly regulated the protein expression of apoptosis-related transcription factors, including c-Jun, IL6, LAMB3, OSMR, STC1, OLR1, SDC4 and PLAU; and 7c also regulated the protein expression of inflammatory cytokines including IL6, CXCL8, TNFSF9, TNFRSF12A and OSMR, and the phosphorylation levels of RelA.

A Novel L-Phenylalanine Dipeptide Inhibits the Growth and Metastasis of Prostate Cancer Cells via Targeting DUSP1 and TNFSF9.

Prostate cancer (PCa) is a common malignant cancer of the urinary system. Drug therapy, chemotherapy, and radical prostatectomy are the primary treatment methods, but drug resistance and postoperative recurrence often occur. Therefore, seeking novel anti-tumor compounds with high efficiency and low toxicity from natural products can produce a new tumor treatment method.

Trifluoromethylpyridine 1,3,4-Oxadiazole Derivatives: Emerging Scaffolds as Bacterial Agents.

A new class of trifluoromethylpyridine 1,3,4-oxadiazole derivatives (-) was obtained, and their antibacterial activities were evaluated. Some of them exhibited good activity, particularly which had the highest in vitro activity against () and pv. ().

A novel 3',5'-diprenylated chalcone induces concurrent apoptosis and GSDME-dependent pyroptosis through activating PKCδ/JNK signal in prostate cancer.

Although androgen deprivation therapy may initially be effective in prostate cancer, the disease can gradually progress to castration-resistant prostate cancer, at which point chemotherapy becomes the major clinical strategy. In this study, we demonstrated the anti-cancer potential of a novel 3',5'-diprenylated chalcone (C10), which selectively inhibited the proliferation of PC3 cells and . C10 treatment elevated the proportion of PC3 cells in sub-G1 phase and induced programmed cell death.

Fli-1 Activation through Targeted Promoter Activity Regulation Using a Novel 3', 5'-diprenylated Chalcone Inhibits Growth and Metastasis of Prostate Cancer Cells.

The friend leukemia integration 1 (Fli-1) gene is involved in the expression control of key genes in multiple pathogenic/physiological processes, including cell growth, differentiation, and apoptosis; this implies that Fli-1 is a strong candidate for drug development. In our previous study, a 3',5'-diprenylated chalcone, (E)-1-(2-hydroxy-4-methoxy-3,5-diprenyl) phenyl-3-(3-pyridinyl)-propene-1-one (), was identified as a novel anti-prostate cancer (PCa) agent. Here, we investigated the molecular mechanisms underlying the anti-cancer effects of on the growth, metastasis, and invasion of PC3 cells in vitro.

A novel synthesized 3', 5'-diprenylated chalcone mediates the proliferation of human leukemia cells by regulating apoptosis and autophagy pathways.

Leukemia is a hematologic malignancy with poor prognosis in humans and chemotherapy is the main strategy for treating leukemia patients. Novel drugs with better selectivity and lower toxicity are required for the treatment of patients. A novel 3',5'-diprenylated chalcone, (E)-1-(2-hydroxy-4-methoxy-3,5-diprenyl) phenyl-3-(3- pyridinyl)-propene-1-one (C10) is a potential new anti-leukemia agent.

Novel 3',5'-diprenylated chalcones inhibited the proliferation of cancer cells in vitro by inducing cell apoptosis and arresting cell cycle phase.

A double Claisen rearrangements synthetic strategy was established for the total synthesis of 4,4'-dimethyl medicagenin (compound 6c). A series of its analogs also were prepared, including two novel 3',5'-diprenylated chalcones, in which ring B was replaced by azaheterocycle. The structures of the twenty-two newly synthesized compounds were confirmed by H NMR, C NMR and ESI-MS.