Pub Date : 2025-01-30DOI: 10.1016/j.bmcl.2025.130115
Demyd S. Milokhov , Mykola O. Balabushko , Anna Y. Kolomiets , Sofiia D. Rabotnikova , Pavlo A. Virych , Anton O. Poliudov , Svitlana V. Shishkina , Yulian M. Volovenko , Alexey V. Dobrydnev
Herein we describe efficient and cost-effective synthesis of azo-based and aminomethylene derivatives of cyclic β-keto sulfones, specifically, 4,4-disubstituted (E)-2-(2-phenylhydrazineylidene)dihydrothiophen-3(2H)-one 1,1-dioxides and 4,4-disubstituted (E)-2-((methylamino)methylene)dihydrothiophen-3(2H)-one 1,1-dioxides. The azo-based derivatives were prepared through the azo coupling of cyclic β-keto sulfones with aromatic diazonium acetates, in situ prepared by diazotization of appropriate substituted amino benzenes. The aminomethylene derivatives were synthesized through the condensation of cyclic β-keto sulfones with DMF-DMA followed by a transamination reaction with primary amines. The target products were obtained in good yields and their structure was unambiguously established based on NMR spectra data, X-ray diffraction study, and DFT calculations. These compounds were designed as cost-effective and multitarget biologically active compounds. Further in vitro study showed antibacterial activity against Staphylococcus aureus and cytotoxicity against the MDA-MB-231 breast cancer cell line without affecting non-malignant cells MAEC. The molecular docking study confirmed good binding affinity of the studied compounds for DHPS, crucial for the bacterial life cycle and for CLK4 and IDO1, which are the therapeutic targets in cancer treatment.
{"title":"Synthesis, antibacterial and anticancer activity of azo-based and aminomethylene derivatives of cyclic β-keto sulfones","authors":"Demyd S. Milokhov , Mykola O. Balabushko , Anna Y. Kolomiets , Sofiia D. Rabotnikova , Pavlo A. Virych , Anton O. Poliudov , Svitlana V. Shishkina , Yulian M. Volovenko , Alexey V. Dobrydnev","doi":"10.1016/j.bmcl.2025.130115","DOIUrl":"10.1016/j.bmcl.2025.130115","url":null,"abstract":"<div><div>Herein we describe efficient and cost-effective synthesis of azo-based and aminomethylene derivatives of cyclic β-keto sulfones, specifically, 4,4-disubstituted (<em>E</em>)-2-(2-phenylhydrazineylidene)dihydrothiophen-3(2<em>H</em>)-one 1,1-dioxides and 4,4-disubstituted (<em>E</em>)-2-((methylamino)methylene)dihydrothiophen-3(2<em>H</em>)-one 1,1-dioxides. The azo-based derivatives were prepared through the azo coupling of cyclic β-keto sulfones with aromatic diazonium acetates, <em>in situ</em> prepared by diazotization of appropriate substituted amino benzenes. The aminomethylene derivatives were synthesized through the condensation of cyclic β-keto sulfones with DMF-DMA followed by a transamination reaction with primary amines. The target products were obtained in good yields and their structure was unambiguously established based on NMR spectra data, X-ray diffraction study, and DFT calculations. These compounds were designed as cost-effective and multitarget biologically active compounds. Further <em>in vitro</em> study showed antibacterial activity against <em>Staphylococcus aureus</em> and cytotoxicity against the MDA-MB-231 breast cancer cell line without affecting non-malignant cells MAEC. The molecular docking study confirmed good binding affinity of the studied compounds for DHPS, crucial for the bacterial life cycle and for CLK4 and IDO1, which are the therapeutic targets in cancer treatment.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130115"},"PeriodicalIF":2.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-30DOI: 10.1016/j.bmcl.2025.130118
Eduardo F.A. Fernandes , Line B.S. Knudsen , Andreas Kjaer , Kristian Strømgaard , Matthias M. Herth
The absence of universal and expedient labeling procedures hampers the widespread application of peptides as molecular tracers for positron emission tomography (PET). In this work, we have developed a proof-of-concept direct radiofluorination procedure for peptides using conventional solid-phase peptide synthesis. The method is compatible with all standard amino acids and enables the generation of a range of peptide-based radiopharmaceuticals archieving radiochemical yields of up to 30 % and radiochemical purities above 95 %.
{"title":"Solid-phase supported direct 18F-radiofluorination of peptides","authors":"Eduardo F.A. Fernandes , Line B.S. Knudsen , Andreas Kjaer , Kristian Strømgaard , Matthias M. Herth","doi":"10.1016/j.bmcl.2025.130118","DOIUrl":"10.1016/j.bmcl.2025.130118","url":null,"abstract":"<div><div>The absence of universal and expedient labeling procedures hampers the widespread application of peptides as molecular tracers for positron emission tomography (PET). In this work, we have developed a proof-of-concept direct radiofluorination procedure for peptides using conventional solid-phase peptide synthesis. The method is compatible with all standard amino acids and enables the generation of a range of peptide-based radiopharmaceuticals archieving radiochemical yields of up to 30 % and radiochemical purities above 95 %.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130118"},"PeriodicalIF":2.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-30DOI: 10.1016/j.bmcl.2025.130117
Jie Mao , Kaizhen Wang , Jun Tong , Wanheng Zhang, Guoqing Shen, Dexiang Wang, Zepeng Liao, Zhiyi Zhang, Qi Miao, Sheng Jiang, Kuojun Zhang
Simultaneous inhibition of poly(ADP-ribose) polymerase (PARP) and nicotinamide phosphoribosyltransferase (NAMPT) has been shown to be synergistically effective against breast cancer susceptibility (BRCA) wild-type triple-negative breast cancer (TNBC) through synthetic lethality, which may be explored to broaden the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/NAMPT inhibitors through a pharmacophore linking approach. The lead compound 13j with potent inhibitory activity against both PARP1 and NAMPT (IC50= 0.8 and 18 nM, respectively) effectively inhibited the proliferation of TNBC MDA-MB-231 cells with wild-type BRCA at submicromolar level. Mechanically, 13j disrupted the homologous recombination repair (HRR) pathway, caused the accumulation of DNA double-strand breaks (DSBs) and ultimately induced apoptotic cell death. In addition, this compound exhibited potent inhibitory potency on the migration of MDA-MB-231 cells. This study demonstrates that compound 13j is a promising lead compound for the development of better PARP/NAMPT inhibitors to treat TNBC with wild-type BRCA.
{"title":"Discovery of dual PARP/NAMPT inhibitors for the treatment of BRCA wild-type triple-negative breast cancer","authors":"Jie Mao , Kaizhen Wang , Jun Tong , Wanheng Zhang, Guoqing Shen, Dexiang Wang, Zepeng Liao, Zhiyi Zhang, Qi Miao, Sheng Jiang, Kuojun Zhang","doi":"10.1016/j.bmcl.2025.130117","DOIUrl":"10.1016/j.bmcl.2025.130117","url":null,"abstract":"<div><div>Simultaneous inhibition of poly(ADP-ribose) polymerase (PARP) and nicotinamide phosphoribosyltransferase (NAMPT) has been shown to be synergistically effective against breast cancer susceptibility (BRCA) wild-type triple-negative breast cancer (TNBC) through synthetic lethality, which may be explored to broaden the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/NAMPT inhibitors through a pharmacophore linking approach. The lead compound <strong>13j</strong> with potent inhibitory activity against both PARP1 and NAMPT (IC<sub>50</sub> <em>=</em> 0.8 and 18 nM, respectively) effectively inhibited the proliferation of TNBC MDA-MB-231 cells with wild-type BRCA at submicromolar level. Mechanically, <strong>13j</strong> disrupted the homologous recombination repair (HRR) pathway, caused the accumulation of DNA double-strand breaks (DSBs) and ultimately induced apoptotic cell death. In addition, this compound exhibited potent inhibitory potency on the migration of MDA-MB-231 cells. This study demonstrates that compound <strong>13j</strong> is a promising lead compound for the development of better PARP/NAMPT inhibitors to treat TNBC with wild-type BRCA.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130117"},"PeriodicalIF":2.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143072939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-29DOI: 10.1016/j.bmcl.2025.130116
Xinyi Shi , Yumiao Song , Xinyu Zhang , Ling Ding , Huizi Shangguan , Xin Wang , Jiping Liu , Yongheng Shi , Xinya Xu , Yundong Xie
The hepatic injury caused by clofibrate (CF) is strongly associated with oxidative stress and inflammation. This study aims to develop a hypolipidemic compound that possesses antioxidant, anti-inflammatory properties and reduces liver injury. Carvacrol-clofibrate (CF-Carvacrol) was synthesized by optimizing the structure of CF by carvacrol. CF-Carvacrol showed significant lipid-lowering effects in hyperlipidemic mouse models induced by Triton WR 1339. The molecular docking results showed that CF-Carvacrol has a good affinity for PPAR-α. The liver injury study showed that CF-Carvacrol had significantly lower liver injury compared to CF. Manifested as a significant decrease in liver weight and liver coefficient (P < 0.01), as well as a significant decrease in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) (P < 0.01). Histopathology of liver tissue showed that the necrosis of liver cells, cytoplasmic looseness, nuclear degeneration, and infiltration of inflammatory cells were significantly reduced in the CF-Carvacrol group. CF-Carvacrol can significantly up-regulate the expression of Nrf2 and HO-1 in liver (P < 0.05, P < 0.01). The expression of inflammatory factors TNF-α and IL-6 in the liver was significantly down-regulation (P < 0.05, P < 0.01). The levels of superoxide dismutase (SOD) and glutathione (GSH) significantly increased (P < 0.05, P < 0.01), while the content of malondialdehyde (MDA) in lipid peroxidation significantly decreased (P < 0.01). These results revealed that CF-Carvacrol has significant hypolipidemic activity and mild liver injury, and may exert antioxidant and anti-inflammatory activity by activating the Nrf2/HO-1 signaling pathway to reduce liver injury.
{"title":"Optimization of clofibrate by carvacrol results in a new hypolipidemic compound with low hepatic injury","authors":"Xinyi Shi , Yumiao Song , Xinyu Zhang , Ling Ding , Huizi Shangguan , Xin Wang , Jiping Liu , Yongheng Shi , Xinya Xu , Yundong Xie","doi":"10.1016/j.bmcl.2025.130116","DOIUrl":"10.1016/j.bmcl.2025.130116","url":null,"abstract":"<div><div>The hepatic injury caused by clofibrate (CF) is strongly associated with oxidative stress and inflammation. This study aims to develop a hypolipidemic compound that possesses antioxidant, anti-inflammatory properties and reduces liver injury. Carvacrol-clofibrate (CF-Carvacrol) was synthesized by optimizing the structure of CF by carvacrol. CF-Carvacrol showed significant lipid-lowering effects in hyperlipidemic mouse models induced by Triton WR 1339. The molecular docking results showed that CF-Carvacrol has a good affinity for PPAR-α. The liver injury study showed that CF-Carvacrol had significantly lower liver injury compared to CF. Manifested as a significant decrease in liver weight and liver coefficient (<em>P <</em> 0.01), as well as a significant decrease in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) (<em>P <</em> 0.01). Histopathology of liver tissue showed that the necrosis of liver cells, cytoplasmic looseness, nuclear degeneration, and infiltration of inflammatory cells were significantly reduced in the CF-Carvacrol group. CF-Carvacrol can significantly up-regulate the expression of Nrf2 and HO-1 in liver (<em>P <</em> 0.05, <em>P <</em> 0.01). The expression of inflammatory factors TNF-α and IL-6 in the liver was significantly down-regulation (<em>P <</em> 0.05, <em>P <</em> 0.01). The levels of superoxide dismutase (SOD) and glutathione (GSH) significantly increased (<em>P <</em> 0.05, <em>P <</em> 0.01), while the content of malondialdehyde (MDA) in lipid peroxidation significantly decreased (<em>P <</em> 0.01). These results revealed that CF-Carvacrol has significant hypolipidemic activity and mild liver injury, and may exert antioxidant and anti-inflammatory activity by activating the Nrf2/HO-1 signaling pathway to reduce liver injury.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130116"},"PeriodicalIF":2.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.bmcl.2025.130114
Yeju Oh , Da Eun An , Jaebeom Park , Byumseok Koh , Kyung-Jin Cho , Hongjun Jeon
KX-01 (tirbanibulin, Klisyri®) is a recently FDA-approved drug for treating actinic keratosis, with a distinct dual mechanism of action combining microtubule disruption and non-ATP-competitive Src inhibition. This unique mechanism and novel chemotype highlight KX-01′s potential as a payload for antibody-drug conjugates. In this study, we synthesized and evaluated KX-01 derivatives to enhance anticancer potency and explore functional groups suitable for antibody conjugation. Notably, replacing the morpholine group with an N-benzoylpiperazine scaffold resulted in an analog with significantly improved in vitro antiproliferative activity, attributed to enhanced microtubule disruption and Src inhibition. Furthermore, introducing a phenol or aniline functionality as a common linker attachment point preserved substantial cytotoxicity. These results suggest the potential of KX-01 derivatives for future use as ADC payloads.
{"title":"Synthesis and evaluation of KX-01 analogs with an exploration of linker attachment points for antibody-drug conjugates","authors":"Yeju Oh , Da Eun An , Jaebeom Park , Byumseok Koh , Kyung-Jin Cho , Hongjun Jeon","doi":"10.1016/j.bmcl.2025.130114","DOIUrl":"10.1016/j.bmcl.2025.130114","url":null,"abstract":"<div><div>KX-01 (tirbanibulin, Klisyri®) is a recently FDA-approved drug for treating actinic keratosis, with a distinct dual mechanism of action combining microtubule disruption and non-ATP-competitive Src inhibition. This unique mechanism and novel chemotype highlight KX-01′s potential as a payload for antibody-drug conjugates. In this study, we synthesized and evaluated KX-01 derivatives to enhance anticancer potency and explore functional groups suitable for antibody conjugation. Notably, replacing the morpholine group with an <em>N</em>-benzoylpiperazine scaffold resulted in an analog with significantly improved <em>in vitro</em> antiproliferative activity, attributed to enhanced microtubule disruption and Src inhibition. Furthermore, introducing a phenol or aniline functionality as a common linker attachment point preserved substantial cytotoxicity. These results suggest the potential of KX-01 derivatives for future use as ADC payloads.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130114"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.bmcl.2025.130113
Emerson P. Heckler , Liaqat Ali , Shrijan Bhattarai , Brittnee Cagle-White , Nickalus C. Smith , Erik D. Moore , Robert A. Coover , May H. Abdel Aziz , Aurijit Sarkar
Vancomycin intermediate-resistant Staphylococcus aureus (VISA) is a pathogen of concern. VraS, a histidine kinase, facilitates the VISA phenotype. Here, we reveal a benzoxazolyl urea (chemical 1) that directly inhibits VraS and enhances vancomycin to below the clinical breakpoint against an archetypal VISA strain, Mu50. 50 μM of 1 enhances vancomycin 16-fold to 0.25 μg/mL. The MIC of oxacillin is enhanced 32-fold to 8 μg/mL, only slightly above its clinical breakpoint. The chemical also showed promising enhancement of oxacillin against several MRSA strains. 1 shows ∼30 % inhibition of ATPase activity in VraS and reduces vra gene auto-upregulation typical upon vancomycin exposure. Therefore, 1 inhibits VraS to block normal vra operon function, leading to potent enhancement of cell wall-directed antibiotics. Interestingly, a molecular modeling approach suggests 1 does not displace ATP from the active site, but acts elsewhere. While VraS inhibitors have previously been reported to function against MRSA, to the best of our knowledge, this is the first direct VraS inhibitor ever reported that shows significant enhancement of vancomycin against VISA.
{"title":"A benzoxazolyl urea inhibits VraS and enhances antimicrobials against vancomycin intermediate-resistant Staphylococcus aureus","authors":"Emerson P. Heckler , Liaqat Ali , Shrijan Bhattarai , Brittnee Cagle-White , Nickalus C. Smith , Erik D. Moore , Robert A. Coover , May H. Abdel Aziz , Aurijit Sarkar","doi":"10.1016/j.bmcl.2025.130113","DOIUrl":"10.1016/j.bmcl.2025.130113","url":null,"abstract":"<div><div>Vancomycin intermediate-resistant <em>Staphylococcus aureus</em> (VISA) is a pathogen of concern. VraS, a histidine kinase, facilitates the VISA phenotype. Here, we reveal a benzoxazolyl urea (chemical <strong><em>1</em></strong>) that directly inhibits VraS and enhances vancomycin to below the clinical breakpoint against an archetypal VISA strain, Mu50. 50 μM of <strong><em>1</em></strong> enhances vancomycin 16-fold to 0.25 μg/mL. The MIC of oxacillin is enhanced 32-fold to 8 μg/mL, only slightly above its clinical breakpoint. The chemical also showed promising enhancement of oxacillin against several MRSA strains. <strong><em>1</em></strong> shows ∼30 % inhibition of ATPase activity in VraS and reduces <em>vra</em> gene auto-upregulation typical upon vancomycin exposure. Therefore, <strong><em>1</em></strong> inhibits VraS to block normal <em>vra</em> operon function, leading to potent enhancement of cell wall-directed antibiotics. Interestingly, a molecular modeling approach suggests <strong><em>1</em></strong> does not displace ATP from the active site, but acts elsewhere. While VraS inhibitors have previously been reported to function against MRSA, to the best of our knowledge, this is the first direct VraS inhibitor ever reported that shows significant enhancement of vancomycin against VISA.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130113"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.bmcl.2025.130110
Hui Xu , Baohu Li , Kai Tang , Jinfei Yang , Peng Zhan
Nucleoside analogs (NAs), as antiviral drugs, play a significant role in clinical medicine, constituting approximately 50 % of all antiviral therapies in current use. Nucleoside inhibitors function by mimicking the structure of natural nucleosides, integrating themselves into viral genetic material during replication, and subsequently inhibiting the virus’s ability to reproduce. They are used to treat a variety of viral infections, including herpes simplex, hepatitis B, and acquired immunodeficiency syndrome (AIDS). This review offers the development and mechanisms of atypical nucleoside antiviral agents that target novel sites on viral polymerase and other antiviral targets of nucleoside molecules, highlighting their significance in response to emerging viral threats like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
{"title":"Nucleoside antiviral agents with atypical structures and new targets","authors":"Hui Xu , Baohu Li , Kai Tang , Jinfei Yang , Peng Zhan","doi":"10.1016/j.bmcl.2025.130110","DOIUrl":"10.1016/j.bmcl.2025.130110","url":null,"abstract":"<div><div>Nucleoside analogs (NAs), as antiviral drugs, play a significant role in clinical medicine, constituting approximately 50 % of all antiviral therapies in current use. Nucleoside inhibitors function by mimicking the structure of natural nucleosides, integrating themselves into viral genetic material during replication, and subsequently inhibiting the virus’s ability to reproduce. They are used to treat a variety of viral infections, including herpes simplex, hepatitis B, and acquired immunodeficiency syndrome (AIDS). This review offers the development and mechanisms of atypical nucleoside antiviral agents that target novel sites on viral polymerase and other antiviral targets of nucleoside molecules, highlighting their significance in response to emerging viral threats like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130110"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.bmcl.2025.130112
Jaquelin Aroujo , Haleigh Parker , Angela Boari , Evan Mason , Mackenzie U. Otakpor , Tania Betancourt , Alexander Kornienko , Maria Letizia Ciavatta , Marianna Carbone , Antonio Evidente , Joseph H. Taube , Daniel Romo
To gain further insights into the importance of the unsaturated 1,4-ketoaldehyde moiety of ophiobolin A (OpA) for the potency and selectivity observed toward cancer stem cells, several derivatives were synthesized through controlled reduction and oxidations of the unsaturated aldehyde and ketone moieties. Structure elucidation of these new OpA derivatives was achieved through detailed NMR studies and comparison to OpA and known isolated congeners possessing variations in these regions. The relative stereochemistry of the newly generated stereocenters was determined by coupling constants in conjunction with conformational analyses (DFT) of the synthetic derivatives. The cytotoxicity of these derivatives was studied against breast cancer and glioblastoma cell lines possessing stem-cell like properties. In addition, the comparative activity toward HMLE and HMLE-TWIST mammary epithelial cells was studied, with the latter cell line representing an epithelial mesenchymal transition positive (EMT+) cell line.
{"title":"Derivatization of ophiobolin A and cytotoxicity toward breast and glioblastoma cancer stem cells: Varying the ketone and unsaturated aldehyde moieties","authors":"Jaquelin Aroujo , Haleigh Parker , Angela Boari , Evan Mason , Mackenzie U. Otakpor , Tania Betancourt , Alexander Kornienko , Maria Letizia Ciavatta , Marianna Carbone , Antonio Evidente , Joseph H. Taube , Daniel Romo","doi":"10.1016/j.bmcl.2025.130112","DOIUrl":"10.1016/j.bmcl.2025.130112","url":null,"abstract":"<div><div>To gain further insights into the importance of the unsaturated 1,4-ketoaldehyde moiety of ophiobolin A (OpA) for the potency and selectivity observed toward cancer stem cells, several derivatives were synthesized through controlled reduction and oxidations of the unsaturated aldehyde and ketone moieties. Structure elucidation of these new OpA derivatives was achieved through detailed NMR studies and comparison to OpA and known isolated congeners possessing variations in these regions. The relative stereochemistry of the newly generated stereocenters was determined by coupling constants in conjunction with conformational analyses (DFT) of the synthetic derivatives. The cytotoxicity of these derivatives was studied against breast cancer and glioblastoma cell lines possessing stem-cell like properties. In addition, the comparative activity toward HMLE and HMLE-TWIST mammary epithelial cells was studied, with the latter cell line representing an epithelial mesenchymal transition positive (EMT<sup>+</sup>) cell line.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130112"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-24DOI: 10.1016/j.bmcl.2025.130111
Thomas O. Schrader , Kym I. Lorrain , Matthew R. Nelli , Yu Xue , Yong Chen , Alexander Broadhead , Christopher Baccei , Austin Chen
Novel kappa opioid receptor (KOR) agonists that preferentially activate G-protein signaling versus β-arrestin-2 recruitment are described. Starting from a literature-reported phenol-containing diphenethylamine KOR agonist, structure–activity relationship (SAR) studies revealed replacement of the phenol with various non-hydroxylated bicyclic heteroaromatics led to tertiary diarylethylamines which retained KOR agonist activity and improved metabolic stability in human liver microsomes. Further optimizations produced compound 39, a potent activator of G-protein signaling (GTPγS EC50 = 14 nM, 83 % Emax) that did not elicit a β-arrestin-2 recruitment functional response (Emax < 10 %). Compound 39 demonstrated moderate to high intrinsic clearance in human hepatocytes and low potential for Pgp-mediated efflux when evaluated in the MDR1-MDCK permeability assay. Compound 39 exhibited 60- and 810-fold selectivities versus the related mu (MOR) and delta (DOR) opioid receptors in recombinant radioligand binding (Ki) assays. These findings highlight compound 39 and related structures as potential leads toward safe and tolerable therapeutics that target central nervous system (CNS) disorders for which KOR agonism could provide benefit.
{"title":"Novel tertiary diarylethylamines as functionally selective agonists of the kappa opioid receptor","authors":"Thomas O. Schrader , Kym I. Lorrain , Matthew R. Nelli , Yu Xue , Yong Chen , Alexander Broadhead , Christopher Baccei , Austin Chen","doi":"10.1016/j.bmcl.2025.130111","DOIUrl":"10.1016/j.bmcl.2025.130111","url":null,"abstract":"<div><div>Novel kappa opioid receptor (KOR) agonists that preferentially activate G-protein signaling versus <em>β</em>-arrestin-2 recruitment are described. Starting from a literature-reported phenol-containing diphenethylamine KOR agonist, structure–activity relationship (SAR) studies revealed replacement of the phenol with various non-hydroxylated bicyclic heteroaromatics led to tertiary diarylethylamines which retained KOR agonist activity and improved metabolic stability in human liver microsomes. Further optimizations produced compound <strong>39</strong>, a potent activator of G-protein signaling (GTPγS EC<sub>50</sub> = 14 nM, 83 % <em>E</em><sub>max</sub>) that did not elicit a <em>β</em>-arrestin-2 recruitment functional response (<em>E</em><sub>max</sub> < 10 %). Compound <strong>39</strong> demonstrated moderate to high intrinsic clearance in human hepatocytes and low potential for Pgp-mediated efflux when evaluated in the MDR1-MDCK permeability assay. Compound <strong>39</strong> exhibited 60- and 810-fold selectivities versus the related mu (MOR) and delta (DOR) opioid receptors in recombinant radioligand binding (<em>K</em><sub>i</sub>) assays. These findings highlight compound <strong>39</strong> and related structures as potential leads toward safe and tolerable therapeutics that target central nervous system (CNS) disorders for which KOR agonism could provide benefit.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130111"},"PeriodicalIF":2.5,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-23DOI: 10.1016/j.bmcl.2025.130108
Gabrielle Martinez, Kirsten Tolentino, Paridhi Sukheja, Jasmine Webb, Case W. McNamara, Arnab K. Chatterjee, Baiyuan Yang
Screening of the ChemDiv molecular library in cholesterol media against Mycobacterium tuberculosis (Mtb) H37Rv strain identified a novel isoxazole thiophene hit as a putative Rv1625c/Cya activator with a promising in vitro activity and good pharmacokinetic properties. Twenty-nine analogs were synthesized to assess the structure–activity relationships (SAR) to further improve potency. The most notable analog was P15, which showed an intramacrophage EC50 = 1.96 µM and exhibited 58.0 % oral bioavailability when it was dosed orally at 20 mg/kg in a mouse pharmacokinetic (PK) study. The overall medicinal chemistry campaign revealed limited SAR that did not support further investigation into this series.
{"title":"Novel isoxazole thiophene-containing compounds active against Mycobacterium tuberculosis","authors":"Gabrielle Martinez, Kirsten Tolentino, Paridhi Sukheja, Jasmine Webb, Case W. McNamara, Arnab K. Chatterjee, Baiyuan Yang","doi":"10.1016/j.bmcl.2025.130108","DOIUrl":"10.1016/j.bmcl.2025.130108","url":null,"abstract":"<div><div>Screening of the ChemDiv molecular library in cholesterol media against <em>Mycobacterium tuberculosis</em> (Mtb) H37Rv strain identified a novel isoxazole thiophene hit as a putative Rv1625c/Cya activator with a promising <em>in vitro</em> activity and good pharmacokinetic properties. Twenty-nine analogs were synthesized to assess the structure–activity relationships (SAR) to further improve potency. The most notable analog was P15, which showed an intramacrophage EC<sub>50</sub> = 1.96 µM and exhibited 58.0 % oral bioavailability when it was dosed orally at 20 mg/kg in a mouse pharmacokinetic (PK) study. The overall medicinal chemistry campaign revealed limited SAR that did not support further investigation into this series.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130108"},"PeriodicalIF":2.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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