Bioorganic & Medicinal Chemistry Letters

Design, synthesis and biological evaluation of novel HIF-1α PROTACs degrader as potent anti-cervical cancer agents

Cervical cancer is the fourth most common and deadly cancer globally. Hypoxia-inducible factor-1α (HIF-1α) plays a key promoter of tumor progression and treatment resistance, making it an important anticancer target. Here, we designed and synthesized a series of novel HIF-1α-targeting PROTAC degraders based on LW-6 and its derivative W-1. Among them, Z12 showed the strongest anti-proliferative and HIF1α degradation activities in HeLa cells. Z12 promoted HIF-1α degradation via the ubiquitin-proteasome pathway by facilitating the formation of a HIF-1α/VHL ternary complex. Furthermore, Z12 inhibited HeLa cell proliferation, migration, and colony formation, induced apoptosis, and reduced p-MEK and p-AKT expression in the MAPK and PI3K/AKT pathways. This work offers a promising strategy for developing HIF1α-PROTAC degraders and treating cervical cancer.

PFKFB4 modulated by miR-195-5p can boost the malignant progression of cervical cancer cells

PFKFB4 is dysregulated in varying tumors and has the biological function of regulating tumor progression. However, its biological function in cervical cancer is poorly understood. We obtained the upstream regulatory gene (miR-195-5p) of PFKFB4 through bioinformatics analysis. Then, experiments were introduced to measure expression and targeting relationship of miR-195-5p and PFKFB4 in cervical cancer cells, in order to evaluate their influence on proliferation, migration, invasion and angiogenesis of cervical cancer cells. As expressed in results, PFKFB4 was abnormally increased and boosted malignant progression of cervical cancer cells. Besides, miR-195-5p was markedly decreased and restrained PFKFB4 in cervical cancer. While tumor-suppressive effect of miR-195-5p was partially restored by overexpressing PFKFB4, indicating that miR-195-5p and PFKFB4 may be new therapeutic targets for cervical cancer patients.

Synthesis of Isosteviol derivatives as potential anticancer agents, especially for ovarian Cancer: In vitro cytotoxicity, cell cycle arrest, network pharmacology and molecular docking study

Isosteviol is a tetracyclic diterpenoid from the hydrolysis of steviosidic acid, it exhibits a moderate inhibitory impact on tumor proliferation across various cancer types. Herein, we improved antitumor efficacy of isosteviol by modifying its reactive groups at C-16 and C-19 positions. A series of isosteviol derivatives 2-17, were synthesized and characterized. Their anti-proliferative activities were evaluated in three human cancer cell lines (HCT116, SKOV3 and HepG2) by CCK-8 assay. The results showed that derivative 10 has strong cancer cell inhibitory activities (with IC

Repurposing of antipsychotics perphenazine for the treatment of endometrial cancer

Endometrial cancer (EC) is one of the most common and fatal gynecological cancers worldwide, but there is no effective treatment for the EC patients of progesterone resistance. Repurposing of existing drugs is a good strategy to discover new candidate drugs. In this text, perphenazine (PPZ), approved for psychosis therapy, was identified as a potential agent for the treatment of both progesterone sensitive and resistant endometrial cancer for the first time. Specifically, perphenazine exhibited good cell proliferation inhibition in Ishikawa (ISK) and KLE cell lines according to the CCK-8 assay and colony formation assay. It also reduced the cell migration of ISK and KLE cell lines in the light of the transwell migration assay. Annexin-V/PI double staining assay suggested that perphenazine could effectively induce ISK and KLE cell apoptosis. Moreover, results of western blot assay indicated perphenazine obviously inhibited the phosphorylation of Akt. Delightedly, PPZ also could significantly attenuate xenograft tumor growth at both 3 mg/kg and 15 mg/kg in mice without influencing the body weights.

Aptamer-modified GSH-degradable honokiol polyprodrug nanoparticles for ovarian cancer-specific targeting therapy

Honokiol (HK) is a polyphenol isolated from the Magnolia genus, a component of traditional Chinese herbal medicine, which can effectively suppress the growth of various tumors, including ovarian cancer. However, its low water solubility and lack of tumor-targeting ability have greatly hindered the clinical application of HK. Herein, a glutathione (GSH)-sensitive HK polyprodrug was prepared using HK as the backbone. An EpCAM-specific aptamer and poly(ethylene glycol) (PEG) were then conjugated to the HK polyprodrug, and the resulting polyprodrug was assembled into nanoparticles (NPs) in water. The HK polyprodrug-formed NPs achieved high drug loading and GSH-responsive drug release. Moreover, after optimization, HK polyprodrug NPs (A/P-PHK NP40), formed by aptamer-modified and PEG-modified prodrug at a feed molar ratio of 2: 3, exhibited the highest ability to target EpCAM-overexpressing ovarian cancer cells. A/P-PHK NP40 also demonstrated a greater cell growth inhibition effect in ovarian cancer cells compared to free HK and control HK NPs. All in all, this work reported a novel strategy for HK delivery based on microenvironment responsiveness polyprodrug, which provided a potential method for ovarian cancer targeting therapy.

Cytotoxic leuconoxine-type diazaspiroindole alkaloids isolated from Cryptolepis dubia

Two leuconoxine-type diazaspiroindole alkaloids, the known compound, (+)-melodinine E (1), and its new analogue, (+)-11-chloromelodinine E (2), were isolated from the stems of Cryptolepis dubia (Burm.f.) M.R. Almeida (Apocynaceae), collected in Laos. The chemical structures of these compounds were determined by analysis of their spectroscopic data and by comparison of these data with literature values, of which the molecular structure of 1 has been determined previously by analysis of its single-crystal X-ray diffraction data. The absolute configurations of 1 and 2 have been defined by their experimental and simulated electronic circular dichroism (ECD) spectroscopic data and supported by

Discovery and characterization of a novel glucose-6-phosphate dehydrogenase (G6PD) inhibitor via high-throughput screening

Altered glucose-6-phosphate dehydrogenase (G6PD) status is influential in many cellular pathophysiological processes and diseases, making G6PD a potential target for cancer therapy. However, the available G6PD inhibitors are very limited and restricted. Here we developed a reducing equivalent nicotinamide adenine dinucleotide phosphate (NADPH) absorption photometry assay based on enzyme kinetics to characterize G6PD activity. In this way, we performed a high-throughput screening (HTS) to an in house library. And then we identified compound named Wedelolactone inhibiting G6PD strongly in a non-competitive, reversible way. In addition, we did the surface Plasmon Resonance (SPR) assay and indicated the K

Cytotoxic effects of kinetin riboside and its selected analogues on cancer cell lines

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Discovery of potent NAMPT-Targeting PROTACs using FK866 as the warhead

Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for cancer therapy due to its strong correlation with nicotinamide adenine dinucleotide (NAD