Lysosome-targeted Aza-BODIPY photosensitizers for anti-cancer photodynamic therapy
In this study, we synthesized N, N-diethylaminomethylphenyl-containing Aza-BODIPY photosensitizers and comprehensively investigated their photophysical/photochemical properties, as well as cell-based and animal-based anti-tumor studies. Among them, BDP 1 has strong NIR absorption at 680 nm and higher singlet oxygen yield in PBS which showed favorable pH-activatable and lysosome-targeting ability. BDP 1 could be easily taken up by tumor cells and showed negligible dark activity (IC50 > 50 μM), however strong phototoxicity upon exposure to light irradiation. The acceptable fluorescence emission from BDP 1 allowed conveni...
Source: Bioorganic and Medicinal Chemistry - January 10, 2024 Category: Chemistry Authors: Mei Hu Xiaochun Dong Weili Zhao Source Type: research
A new small molecule DoNA binding to CAG repeat RNA
Bioorg Med Chem. 2024 Jan 15;98:117580. doi: 10.1016/j.bmc.2023.117580. Epub 2023 Dec 25.ABSTRACTWe here report a new molecule DoNA binding to a CAG repeat RNA. DoNA is a dimer of the NA molecule that we previously reported. NA binds with high affinity to a CAG repeat DNA but not significantly to a CAG repeat RNA. Binding analyses using SPR and CSI-TOF MS indicated a significant increase in the affinity of DoNA to a single stranded CAG repeat RNA compared to NA. Systematic investigation of the RNA motifs bound by DoNA using hairpin RNA models revealed that DoNA binds to the CAG units at overhang and terminal positions, and...
Source: Bioorganic and Medicinal Chemistry - January 9, 2024 Category: Chemistry Authors: Qingwen Chen Takeshi Yamada Koichi Miyagawa Asako Murata Mitsuo Shoji Kazuhiko Nakatani Source Type: research
A new small molecule DoNA binding to CAG repeat RNA
Bioorg Med Chem. 2023 Dec 25;98:117580. doi: 10.1016/j.bmc.2023.117580. Online ahead of print.ABSTRACTWe here report a new molecule DoNA binding to a CAG repeat RNA. DoNA is a dimer of the NA molecule that we previously reported. NA binds with high affinity to a CAG repeat DNA but not significantly to a CAG repeat RNA. Binding analyses using SPR and CSI-TOF MS indicated a significant increase in the affinity of DoNA to a single stranded CAG repeat RNA compared to NA. Systematic investigation of the RNA motifs bound by DoNA using hairpin RNA models revealed that DoNA binds to the CAG units at overhang and terminal positions...
Source: Bioorganic and Medicinal Chemistry - January 9, 2024 Category: Chemistry Authors: Qingwen Chen Takeshi Yamada Koichi Miyagawa Asako Murata Mitsuo Shoji Kazuhiko Nakatani Source Type: research
Discovery of 1,2,3-triazole incorporated indole-piperazines as potent antitubercular agents: Design, synthesis, in vitro biological evaluation, molecular docking and ADME studies
In this report, a library consisting of three sets of indole-piperazine derivatives was designed through the molecular hybridization approach. In total, fifty new hybrid compounds (T1-T50) were synthesized and screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Five (T36, T43, T44, T48 and T49) among fifty compounds exhibited significant inhibitory potency with the MIC of 1.6 µg/mL, which is twofold more potent than the standard first-line TB drug Pyrazinamide and equipotent with Isoniazid. N-1,2,3-triazolyl indole-piperazine derivatives displayed improved inhibition activity...
Source: Bioorganic and Medicinal Chemistry - January 7, 2024 Category: Chemistry Authors: Rajkumar Reddyrajula Umadevi Etikyala Vijjulatha Manga Udaya Kumar Dalimba Source Type: research
Discovery of 1,2,3-triazole incorporated indole-piperazines as potent antitubercular agents: Design, synthesis, in vitro biological evaluation, molecular docking and ADME studies
In this report, a library consisting of three sets of indole-piperazine derivatives was designed through the molecular hybridization approach. In total, fifty new hybrid compounds (T1-T50) were synthesized and screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Five (T36, T43, T44, T48 and T49) among fifty compounds exhibited significant inhibitory potency with the MIC of 1.6 µg/mL, which is twofold more potent than the standard first-line TB drug Pyrazinamide and equipotent with Isoniazid. N-1,2,3-triazolyl indole-piperazine derivatives displayed improved inhibition activity...
Source: Bioorganic and Medicinal Chemistry - January 7, 2024 Category: Chemistry Authors: Rajkumar Reddyrajula Umadevi Etikyala Vijjulatha Manga Udaya Kumar Dalimba Source Type: research
Discovery of ASP6918, a KRAS G12C inhibitor: Synthesis and structure-activity relationships of 1-{2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one derivatives as covalent inhibitors with good potency and oral activity for the treatment of solid tumors
In this report, we further optimized the substituents on the quinazoline scaffold based on the structure-based drug design from the co-crystal structure analysis of compound 1 and KRAS G12C to enhance in vitro activity. As a result, ASP6918 was found to exhibit extremely potent in vitro activity and induce dose-dependent tumor regression in an NCI-H1373 xenograft mouse model after oral administration.PMID:38176113 | DOI:10.1016/j.bmc.2023.117581 (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - January 4, 2024 Category: Chemistry Authors: Tomoyoshi Imaizumi Itsuro Shimada Yoshiki Satake Susumu Yamaki Takanori Koike Takahiro Nigawara Osamu Kaneko Yasushi Amano Kenichi Mori Yosuke Yamanaka Ayako Nakayama Yoshihiro Nishizono Masashi Shimazaki Takeyuki Nagashima Kazuyuki Kuramoto Source Type: research
Discovery of ASP6918, a KRAS G12C inhibitor: Synthesis and structure-activity relationships of 1-{2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one derivatives as covalent inhibitors with good potency and oral activity for the treatment of solid tumors
In this report, we further optimized the substituents on the quinazoline scaffold based on the structure-based drug design from the co-crystal structure analysis of compound 1 and KRAS G12C to enhance in vitro activity. As a result, ASP6918 was found to exhibit extremely potent in vitro activity and induce dose-dependent tumor regression in an NCI-H1373 xenograft mouse model after oral administration.PMID:38176113 | DOI:10.1016/j.bmc.2023.117581 (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - January 4, 2024 Category: Chemistry Authors: Tomoyoshi Imaizumi Itsuro Shimada Yoshiki Satake Susumu Yamaki Takanori Koike Takahiro Nigawara Osamu Kaneko Yasushi Amano Kenichi Mori Yosuke Yamanaka Ayako Nakayama Yoshihiro Nishizono Masashi Shimazaki Takeyuki Nagashima Kazuyuki Kuramoto Source Type: research
Discovery of ASP6918, a KRAS G12C inhibitor: Synthesis and structure-activity relationships of 1-{2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one derivatives as covalent inhibitors with good potency and oral activity for the treatment of solid tumors
In this report, we further optimized the substituents on the quinazoline scaffold based on the structure-based drug design from the co-crystal structure analysis of compound 1 and KRAS G12C to enhance in vitro activity. As a result, ASP6918 was found to exhibit extremely potent in vitro activity and induce dose-dependent tumor regression in an NCI-H1373 xenograft mouse model after oral administration.PMID:38176113 | DOI:10.1016/j.bmc.2023.117581 (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - January 4, 2024 Category: Chemistry Authors: Tomoyoshi Imaizumi Itsuro Shimada Yoshiki Satake Susumu Yamaki Takanori Koike Takahiro Nigawara Osamu Kaneko Yasushi Amano Kenichi Mori Yosuke Yamanaka Ayako Nakayama Yoshihiro Nishizono Masashi Shimazaki Takeyuki Nagashima Kazuyuki Kuramoto Source Type: research
Design, synthesis, and biological evaluation of 2-(naphthalen-1-yloxy)-N-phenylacetamide derivatives as TRPM4 inhibitors for the treatment of prostate cancer
Bioorg Med Chem. 2023 Dec 28;98:117584. doi: 10.1016/j.bmc.2023.117584. Online ahead of print.ABSTRACTTransient receptor potential melastatin 4 (TRPM4) is considered to be a potential target for cancer and other human diseases. Herein, a series of 2-(naphthalen-1-yloxy)-N-phenylacetamide derivatives were designed and synthesized as new TRPM4 inhibitors, aiming to improve cellular potency. One of the most promising compounds, 7d (ZX08903), displayed promising antiproliferative activity against prostate cancer cell lines. 7d also suppressed colony formation and the expression of androgen receptor (AR) protein in prostate can...
Source: Bioorganic and Medicinal Chemistry - January 3, 2024 Category: Chemistry Authors: Le Niu Huina Liu Xiaomei Li Lin Wang Hui Hua Qiaofeng Cao Qiuping Xiang Ting Cai Dongsheng Zhu Source Type: research
Structural optimization of a lysine demethylase 5 inhibitor for improvement of its cellular activity
In this study, we investigated 2a and KDM5-C70 (3a), a prodrug of 2a, and attempted to improve its cellular activity by replacing the N,N-dimethyl amino group of 3a with more lipophilic groups. N-Butyl, N-methyl amino compound 2e exhibited potent and selective KDM5-inhibitory activity equal to that of 2a. Furthermore, the cell membrane permeability of 3e, an ethyl ester prodrug of 2e, was six times higher than that of 3a in a parallel artificial membrane permeation assay. In addition, western blot analysis indicated that treating human lung cancer A549 cells with 3e increased histone methylation levels more strongly than t...
Source: Bioorganic and Medicinal Chemistry - January 3, 2024 Category: Chemistry Authors: Mitsuhiro Terao Yasunobu Yamashita Yuri Takada Yukihiro Itoh Takayoshi Suzuki Source Type: research
Ferroptosis and its modulators: A raising target for cancer and Alzheimer's disease
Bioorg Med Chem. 2023 Dec 20;98:117564. doi: 10.1016/j.bmc.2023.117564. Online ahead of print.ABSTRACTThe process of ferroptosis, a recently identified form of regulated cell death (RCD) is associated with the overloading of iron species and lipid-derived ROS accumulation. Ferroptosis is induced by various mechanisms such as inhibiting system Xc, glutathione depletion, targeting excess iron, and directly inhibiting GPX4 enzyme. Also, ferroptosis inhibition is achieved by blocking excessive lipid peroxidation by targeting different pathways. These mechanisms are often related to the pathophysiology and pathogenesis of disea...
Source: Bioorganic and Medicinal Chemistry - January 3, 2024 Category: Chemistry Authors: Gourav Singh Prashant Kesharwani Gireesh Kumar Singh Saroj Kumar Anjaneyulu Putta Gyan Modi Source Type: research
Novel mitochondrial and DNA damaging fluorescent Calix[4]arenes bearing isatin groups as aromatase inhibitors: Design, synthesis and anticancer activity
Bioorg Med Chem. 2023 Dec 30;98:117586. doi: 10.1016/j.bmc.2023.117586. Online ahead of print.ABSTRACTBreast cancer causes a high rate of mortality all over the world. Therefore, the present study focuses on the anticancer activity of new lower rim-functionalized calix[4]arenes integrated with isatin and the p-position of calixarenes with 1,4-dimethylpyridinium iodine against various human cancer cells such as MCF-7 and MDA-MB-231 breast cancer cell lines, as well as the PNT1A healthy epithelial cell line. It was observed that compound 6c had the lowest values in MCF-7 (8.83 µM) and MDA-MB-231 (3.32 µM). Cell imaging and...
Source: Bioorganic and Medicinal Chemistry - January 3, 2024 Category: Chemistry Authors: Alev Oguz Begum Nurpelin Saglik Mehmet Oguz Bahadir Ozturk Mustafa Yilmaz Source Type: research
Design, synthesis, and anti-cancer evaluation of C-14 arylcarbamate derivatives of andrographolide
In this study, we explored a concise and mild synthetic route to produce novel C-14 arylcarbamate derivatives of andrographolide, a known anti-inflammatory and anticancer natural product. Upon assessing their anti-cancer efficacy against pancreatic ductal adenocarcinoma (PDAC) cells, some derivatives showed stronger cytotoxicity against PANC-1 cells than andrographolide. In addition, we demonstrated one derivative, compound 3m, effectively reduced the expression of oncogenic p53 mutant proteins (p53R273H and p53R248W), proliferation, and migration in PDAC lines, PANC-1 and MIA PaCa-2. Accordingly, the novel derivative hold...
Source: Bioorganic and Medicinal Chemistry - January 3, 2024 Category: Chemistry Authors: Tzu-Ching Yang Yun-Jou Chiang Po-Yu Chiang Han-Yu Chen Kai-Ru Zhuang Yu-Chia Wang Chao-Hsiung Lin Lee-Chiang Lo Shu-Ling Fu Source Type: research
Design, synthesis, and biological evaluation of 2-(naphthalen-1-yloxy)-N-phenylacetamide derivatives as TRPM4 inhibitors for the treatment of prostate cancer
Bioorg Med Chem. 2023 Dec 28;98:117584. doi: 10.1016/j.bmc.2023.117584. Online ahead of print.ABSTRACTTransient receptor potential melastatin 4 (TRPM4) is considered to be a potential target for cancer and other human diseases. Herein, a series of 2-(naphthalen-1-yloxy)-N-phenylacetamide derivatives were designed and synthesized as new TRPM4 inhibitors, aiming to improve cellular potency. One of the most promising compounds, 7d (ZX08903), displayed promising antiproliferative activity against prostate cancer cell lines. 7d also suppressed colony formation and the expression of androgen receptor (AR) protein in prostate can...
Source: Bioorganic and Medicinal Chemistry - January 3, 2024 Category: Chemistry Authors: Le Niu Huina Liu Xiaomei Li Lin Wang Hui Hua Qiaofeng Cao Qiuping Xiang Ting Cai Dongsheng Zhu Source Type: research
Structural optimization of a lysine demethylase 5 inhibitor for improvement of its cellular activity
In this study, we investigated 2a and KDM5-C70 (3a), a prodrug of 2a, and attempted to improve its cellular activity by replacing the N,N-dimethyl amino group of 3a with more lipophilic groups. N-Butyl, N-methyl amino compound 2e exhibited potent and selective KDM5-inhibitory activity equal to that of 2a. Furthermore, the cell membrane permeability of 3e, an ethyl ester prodrug of 2e, was six times higher than that of 3a in a parallel artificial membrane permeation assay. In addition, western blot analysis indicated that treating human lung cancer A549 cells with 3e increased histone methylation levels more strongly than t...
Source: Bioorganic and Medicinal Chemistry - January 3, 2024 Category: Chemistry Authors: Mitsuhiro Terao Yasunobu Yamashita Yuri Takada Yukihiro Itoh Takayoshi Suzuki Source Type: research
