Pub Date : 2025-02-01DOI: 10.1016/j.tet.2024.134423
Binbin Zhou , Huacan Xv , Ke Zhang , Xv Han , Shuhao Liu , Jiayu He , Jinwei Sun , Yuling Li , Yun Liu
A practical synthesis of indolizine-3-carboxylates has been developed via copper-promoted reaction of alkenoic acids with bromoesters and pyridines using air as the terminal oxidant. In this reaction, carboxyl group acts as a traceless substituent to activate carbon-carbon double bond. By this protocol, we have successfully obtained indolizine-3-carboxylates with aryl or alkyl group at 1-position or 2-position of indolizine motif. This protocol features advantages of simple reaction conditions as well as broad substituents kinds.
{"title":"An efficient approach to indolizine-3-carboxylates via Cu(I)-promoted decarboxylative cycloaddition of alkenoic acids","authors":"Binbin Zhou , Huacan Xv , Ke Zhang , Xv Han , Shuhao Liu , Jiayu He , Jinwei Sun , Yuling Li , Yun Liu","doi":"10.1016/j.tet.2024.134423","DOIUrl":"10.1016/j.tet.2024.134423","url":null,"abstract":"<div><div>A practical synthesis of indolizine-3-carboxylates has been developed <em>via</em> copper-promoted reaction of alkenoic acids with bromoesters and pyridines using air as the terminal oxidant. In this reaction, carboxyl group acts as a traceless substituent to activate carbon-carbon double bond. By this protocol, we have successfully obtained indolizine-3-carboxylates with aryl or alkyl group at 1-position or 2-position of indolizine motif. This protocol features advantages of simple reaction conditions as well as broad substituents kinds.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"171 ","pages":"Article 134423"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143181109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tet.2024.134425
Jiaxi Xu
Phosphetane derivatives are a class of four-membered saturated phosphorus-containing heterocycles and have been widely applied as phosphorus-containing chiral ligands in asymmetric catalytic organic reactions. Synthetic methods for phosphetane derivatives are divided mainly into double nucleophilic substitutions, electrophilic addition of phospheniums to olefins and subsequent cyclization, electrophilic ring expansions of cyclopropanes and phosphiranes, cycloaddition and electrocyclic reaction, etc. The scope, limitation, regio- and stereoselectivities, and proposed reaction mechanisms are also discussed for some methods. Further development for preparation of phosphetane derivatives and their application are also prospected.
{"title":"Synthesis of phosphetane derivatives","authors":"Jiaxi Xu","doi":"10.1016/j.tet.2024.134425","DOIUrl":"10.1016/j.tet.2024.134425","url":null,"abstract":"<div><div>Phosphetane derivatives are a class of four-membered saturated phosphorus-containing heterocycles and have been widely applied as phosphorus-containing chiral ligands in asymmetric catalytic organic reactions. Synthetic methods for phosphetane derivatives are divided mainly into double nucleophilic substitutions, electrophilic addition of phospheniums to olefins and subsequent cyclization, electrophilic ring expansions of cyclopropanes and phosphiranes, cycloaddition and electrocyclic reaction, etc. The scope, limitation, regio- and stereoselectivities, and proposed reaction mechanisms are also discussed for some methods. Further development for preparation of phosphetane derivatives and their application are also prospected.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"171 ","pages":"Article 134425"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143182101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tet.2024.134414
Dang Viet Anh , Tran Hong Quang , Ninh Thi Ngoc , Tran Thi Hong Hanh , Nguyen Xuan Cuong , Nguyen Thi Thanh Ngan , Nguyen Ngoc Tung , Nguyen Hoai Nam , Chau Van Minh
Chemical investigation of the mangrove-derived fungus Aspergillus sp. DVXT-221 led to isolation of three undescribed ergot alkaloids, fumigaclavines K−M (1, 2, and 4), and seven known compounds, fumigaclavines I (3), C (5), and E (6), monomethylsulochrin (7), 8′-O-methylasterric acid (8), 2,3′-dimethylosoate (9), and chaetominine (10). Their structures were identified by comprehensive analyses of the spectroscopic methods, including NMR and HRESI mass spectra. The absolute configurations of 1, 2, and 4 were clarified by time-dependent density functional theory (TDDFT) electronic circular dichroism (ECD) spectroscopic analyses. Compound 2 contained the first example of N-methyl oxide among the previously reported ergot alkaloids. Compounds 1 and 3 showed weak cytotoxicity on both HepG2 and MCF7 cell lines, with IC50 values ranging from 61.1 ± 3.1 to 77.2 ± 1.5 μM. Compounds 1 and 9 exhibited stronger inhibitory effect on nitric oxide (NO) production in LPS-stimulated RAW264.7 cells, with IC50 values of 5.3 ± 0.2 and 8.7 ± 0.4 μM, respectively, whereas weaker NO inhibitory effects were observed for 2–4, 8, and 10, with IC50 values ranging from 20.5 ± 0.8 to 36.1 ± 2.3 μM. Both 1 and 9 were suggested to inhibit NO overproduction via down-regulating the action of iNOS protein by molecular docking simulations.
{"title":"Fumigaclavines K−M, undescribed ergot alkaloids from the mangrove-derived fungus Aspergillus sp. DVXT-221 with cytotoxic and NO inhibitory activities","authors":"Dang Viet Anh , Tran Hong Quang , Ninh Thi Ngoc , Tran Thi Hong Hanh , Nguyen Xuan Cuong , Nguyen Thi Thanh Ngan , Nguyen Ngoc Tung , Nguyen Hoai Nam , Chau Van Minh","doi":"10.1016/j.tet.2024.134414","DOIUrl":"10.1016/j.tet.2024.134414","url":null,"abstract":"<div><div>Chemical investigation of the mangrove-derived fungus <em>Aspergillus</em> sp. DVXT-221 led to isolation of three undescribed ergot alkaloids, fumigaclavines K−M (<strong>1</strong>, <strong>2</strong>, and <strong>4</strong>), and seven known compounds, fumigaclavines I (<strong>3</strong>), C (<strong>5</strong>), and E (<strong>6</strong>), monomethylsulochrin (<strong>7</strong>), 8′-O-methylasterric acid (<strong>8</strong>), 2,3′-dimethylosoate (<strong>9</strong>), and chaetominine (<strong>10</strong>). Their structures were identified by comprehensive analyses of the spectroscopic methods, including NMR and HRESI mass spectra. The absolute configurations of <strong>1</strong>, <strong>2</strong>, and <strong>4</strong> were clarified by time-dependent density functional theory (TDDFT) electronic circular dichroism (ECD) spectroscopic analyses. Compound <strong>2</strong> contained the first example of N-methyl oxide among the previously reported ergot alkaloids. Compounds <strong>1</strong> and <strong>3</strong> showed weak cytotoxicity on both HepG2 and MCF7 cell lines, with IC<sub>50</sub> values ranging from 61.1 ± 3.1 to 77.2 ± 1.5 μM. Compounds <strong>1</strong> and <strong>9</strong> exhibited stronger inhibitory effect on nitric oxide (NO) production in LPS-stimulated RAW264.7 cells, with IC<sub>50</sub> values of 5.3 ± 0.2 and 8.7 ± 0.4 μM, respectively, whereas weaker NO inhibitory effects were observed for <strong>2–4</strong>, <strong>8</strong>, and <strong>10</strong>, with IC<sub>50</sub> values ranging from 20.5 ± 0.8 to 36.1 ± 2.3 μM. Both <strong>1</strong> and <strong>9</strong> were suggested to inhibit NO overproduction via down-regulating the action of iNOS protein by molecular docking simulations.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"171 ","pages":"Article 134414"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143181146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tet.2024.134422
Jiahong Chen, Mengke Wang, Weichun Huang, You Zi
A mild and convenient method for synthesizing thioesters has been developed, from sulfenylchlorides and carboxylic acids via a phosphine mediated umpolung process. This approach efficiently produces a broad spectrum of thioesters from readily available carboxylic acids, including primary, secondary, and tertiary types, as well as bioactive molecules. The successful gram-scale reactions also validate its scalability and practical application.
{"title":"An efficient method for thioesterification of carboxylic acid with sulfenylchloride","authors":"Jiahong Chen, Mengke Wang, Weichun Huang, You Zi","doi":"10.1016/j.tet.2024.134422","DOIUrl":"10.1016/j.tet.2024.134422","url":null,"abstract":"<div><div>A mild and convenient method for synthesizing thioesters has been developed, from sulfenylchlorides and carboxylic acids via a phosphine mediated umpolung process. This approach efficiently produces a broad spectrum of thioesters from readily available carboxylic acids, including primary, secondary, and tertiary types, as well as bioactive molecules. The successful gram-scale reactions also validate its scalability and practical application.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"171 ","pages":"Article 134422"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143181116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An efficient synthesis of donor-acceptor type 1,1-bis(sulfonyl)cyclopropanes was achieved using sulfonium salts. The reaction of active bis(sulfonyl)methylene compounds with (1-aryl-2-bromoethyl)dimethylsulfonium bromides and potassium carbonate in aqueous ethyl acetate afforded the corresponding 2-aryl-1,1-bis(sulfonyl)cyclopropanes in good to excellent yields. Furthermore, the synthesis of 2,3-nonsubstituted 1,1-bis(sulfonyl)cyclopropanes from bis(sulfonyl)methanes was also achieved using (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate. The resulting 1,1-bis(sulfonyl)cyclopropanes are expected to serve as versatile small-molecule synthons.
{"title":"Synthesis of donor-acceptor type 1,1-bis(sulfonyl)cyclopropanes from active bis(sulfonyl)methylene compounds using sulfonium salts","authors":"Kotaro Ezoe, Kosuke Murakami, Keisuke Tomohara, Hisanori Nambu","doi":"10.1016/j.tet.2025.134514","DOIUrl":"10.1016/j.tet.2025.134514","url":null,"abstract":"<div><div>An efficient synthesis of donor-acceptor type 1,1-bis(sulfonyl)cyclopropanes was achieved using sulfonium salts. The reaction of active bis(sulfonyl)methylene compounds with (1-aryl-2-bromoethyl)dimethylsulfonium bromides and potassium carbonate in aqueous ethyl acetate afforded the corresponding 2-aryl-1,1-bis(sulfonyl)cyclopropanes in good to excellent yields. Furthermore, the synthesis of 2,3-nonsubstituted 1,1-bis(sulfonyl)cyclopropanes from bis(sulfonyl)methanes was also achieved using (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate. The resulting 1,1-bis(sulfonyl)cyclopropanes are expected to serve as versatile small-molecule synthons.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"175 ","pages":"Article 134514"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tet.2024.134421
Qian Xu, Shunji Zhang, Yuting Li, Xiaoyu Xie, Ran Gao
Herein we disclose the scalable synthesis of 4α-hydroxy-2,5-diene-1-one moiety, which is an essential fragment for the construction of withanolides such as Jaborosalactone B, starting from commercially available 21-hydroxy-20-methylpregn-4-en-3-one (BA) in 10 steps. The synthesis features a 1O2 involved Diels-Alder reaction with 1,3,5-triene to install the 1-hydroxy-4-one in A ring and a Ley's oxidation followed by β-elimination in one pot to furnish the 4α-hydroxy-2,5-diene-1-one moiety.
{"title":"Synthesis of 4α-hydroxy-2,5-diene-1-one framework toward jaborosalactone B","authors":"Qian Xu, Shunji Zhang, Yuting Li, Xiaoyu Xie, Ran Gao","doi":"10.1016/j.tet.2024.134421","DOIUrl":"10.1016/j.tet.2024.134421","url":null,"abstract":"<div><div>Herein we disclose the scalable synthesis of 4α-hydroxy-2,5-diene-1-one moiety, which is an essential fragment for the construction of withanolides such as Jaborosalactone B, starting from commercially available 21-hydroxy-20-methylpregn-4-en-3-one (BA) in 10 steps. The synthesis features a <sup>1</sup>O<sub>2</sub> involved Diels-Alder reaction with 1,3,5-triene to install the 1-hydroxy-4-one in A ring and a Ley's oxidation followed by β-elimination in one pot to furnish the 4α-hydroxy-2,5-diene-1-one moiety.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"171 ","pages":"Article 134421"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143182092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tet.2024.134432
Mariana Budovská , Lucia Očenášová , Peter Očenáš , Radka Michalková , Ján Mojžiš
In this study, we synthesized a minilibrary of twenty-two derivatives of indole phytoalexins containing bromine atom at the position 6 of the indole ring. A short efficient synthesis of novel 6-bromo-1-Boc-brassinin and its amino analogues was achieved, starting from 6-bromo-1H-indole-3-carboxaldehyde in a four-step and a five-step protocol, respectively. In the preparation of the spirocyclic products, electrophilic - nucleophilic 3,2-difunctionalization of the indole core was chosen using bromospirocyclization of 6-bromo-1-Boc-brassinin or thiourea derivatives and subsequent reaction with nucleophiles (methanol or the appropriate aniline). A TFA-promoted cascade reactions of spirocyclic products resulted in the formation of 7-bromocyclobrassinin and its 2-amino analogues. The in vitro antiproliferative activities of prepared compounds were evaluated against a panel of human cancer cell lines and non-malignant cells using the MTT assay and some structure–activity relationships were observed. Results of antiproliferative screening indicated that 3,4-dichlorophenylamino analogue of 6-bromo-1-Boc-brassinin was the most potent (IC50 = 7.1 μM against HCT116 cells, IC50 = 8.8 μM against A549 cells, IC50 = 7.5 μM against Jurkat cells). This compound showed higher antiproliferative activity compared to cisplatin. However, this compound also significantly decreased non-cancer cell proliferation (MCF-10, IC50 = 7.7 μM and Cos-7, IC50 = 12.6 μM). Compounds with 4-(trifluoromethyl)phenylamino and 3,4-dichlorophenylamino moiety tend to have higher IC50 values across multiple cell lines compared to parent compounds with the SCH3 group. The SAR study demonstrated that the incorporation of bromine at the position 6 of indole led to a decrease or loss of activity in most cases.
{"title":"Minilibrary of 6-bromo derivatives of indole phytoalexins: Synthesis, anticancer profile and structure-activity relationship (SAR) study","authors":"Mariana Budovská , Lucia Očenášová , Peter Očenáš , Radka Michalková , Ján Mojžiš","doi":"10.1016/j.tet.2024.134432","DOIUrl":"10.1016/j.tet.2024.134432","url":null,"abstract":"<div><div>In this study, we synthesized a minilibrary of twenty-two derivatives of indole phytoalexins containing bromine atom at the position 6 of the indole ring. A short efficient synthesis of novel 6-bromo-1-Boc-brassinin and its amino analogues was achieved, starting from 6-bromo-1<em>H</em>-indole-3-carboxaldehyde in a four-step and a five-step protocol, respectively. In the preparation of the spirocyclic products, electrophilic - nucleophilic 3,2-difunctionalization of the indole core was chosen using bromospirocyclization of 6-bromo-1-Boc-brassinin or thiourea derivatives and subsequent reaction with nucleophiles (methanol or the appropriate aniline). A TFA-promoted cascade reactions of spirocyclic products resulted in the formation of 7-bromocyclobrassinin and its 2-amino analogues. The <em>in vitro</em> antiproliferative activities of prepared compounds were evaluated against a panel of human cancer cell lines and non-malignant cells using the MTT assay and some structure–activity relationships were observed. Results of antiproliferative screening indicated that 3,4-dichlorophenylamino analogue of 6-bromo-1-Boc-brassinin was the most potent (IC<sub>50</sub> = 7.1 μM against HCT116 cells, IC<sub>50</sub> = 8.8 μM against A549 cells, IC<sub>50</sub> = 7.5 μM against Jurkat cells). This compound showed higher antiproliferative activity compared to cisplatin. However, this compound also significantly decreased non-cancer cell proliferation (MCF-10, IC<sub>50</sub> = 7.7 μM and Cos-7, IC<sub>50</sub> = 12.6 μM). Compounds with 4-(trifluoromethyl)phenylamino and 3,4-dichlorophenylamino moiety tend to have higher IC<sub>50</sub> values across multiple cell lines compared to parent compounds with the SCH<sub>3</sub> group. The SAR study demonstrated that the incorporation of bromine at the position 6 of indole led to a decrease or loss of activity in most cases.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"171 ","pages":"Article 134432"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143182091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tet.2024.134424
Hessa H. Al-Rasheed , Sarah A. Al-Khamis , Assem Barakat , Aliaa A. Masoud , Ahmed A. Sobhy , Doaa A. Ghareeb , Beatriz G. de la Torre , Fernando Albericio , Ayman El-Faham
<div><div>Merging <em>s</em>-triazine and isatin <em>via</em> a hydrazone linkage an efficient strategy to access new potential anticancer derivatives. Consequently, herein we report a new library of fifty new compounds based on isatin-<em>s</em>-triazine hydrazone derivatives. We used a straightforward orthogonal synthetic pathway to prepare disubstituted <em>s</em>-triazine hydrazine derivatives, whose basic structure was modified and then condensed with substituted isatin at the C-5 position to afford the new library of isatin-<em>s</em>-triazine hydrazone derivatives. The newly synthesized compounds were fully characterized by <sup>1</sup>H NMR, <sup>13</sup>C NMR and elemental analysis. The synthesized compounds were evaluated for their antiproliferative activity against lung cancer cell line (A549), and safety profile against Human Caucasian foetal lung (WI-38). The results revealed that all tested compounds exhibited cytotoxic effects against A549 when compared to the reference drug sorafenib. Most of the tested compounds exhibited safety indices that were either equivalent to or higher than sorafenib's index of 11.025, highlighting their superior or comparable safety profiles. Notably, compounds <strong>9a</strong>, <strong>9d</strong>, <strong>10d</strong>, <strong>13a</strong>, <strong>13d</strong>, <strong>14a-14e</strong>, <strong>15a</strong>, <strong>15b</strong>, <strong>15d</strong>, <strong>15e</strong>, and <strong>11a-11e</strong> exhibited particularly promising safety profiles. However, in terms of selectivity, compounds <strong>6a-6e</strong>, <strong>7a-7e, 8a-8e</strong>, <strong>10d</strong>, <strong>12d</strong>, <strong>13a</strong>, <strong>13d</strong>, <strong>14a</strong>, <strong>14d</strong> (with the highest selectivity index), <strong>11c</strong>, and <strong>11d</strong>, <strong>14e</strong>, <strong>15a</strong>, <strong>15b</strong>, <strong>15d</strong>, and <strong>15e</strong> showed greater potency than sorafenib, as evidenced by selectivity indices exceeding 1. In addition, all compounds demonstrated broad-spectrum anti-trypsin properties, five compounds (<strong>7c</strong>, <strong>8a</strong>, <strong>12d</strong>, <strong>13a</strong>, and <strong>13d</strong>) exhibited promising anti-trypsin effects at their anticancer IC<sub>50</sub> values (97.912 ± 12.14, 93.511 ± 10.32, 99.623 ± 14.71, 98.411 ± 25.3, and 75.123 ± 4.32, respectively), while <strong>7c</strong>, <strong>8a</strong>, <strong>12d</strong> and <strong>13a</strong> showed the highest inhibitory effect, surpassing the inhibitory effect of bis(5-amidino-2-benzimidazolyl)methane (IC<sub>50</sub> = 56.617 ± 2.14). When compared to the inhibitory effect of rivaroxaban (53.223 ± 0.98) at a concentration of 0.0013 μM against Factor Xa, all compounds showed lower inhibitory effects except for <strong>6b</strong>, <strong>6c</strong>, <strong>7a</strong>,<strong>7e</strong>, <strong>8a</strong>, <strong>8b</strong>, <strong>8c</strong>, <st
{"title":"Design and synthesis of s-triazine-Isatin hybrids with potent anticancer activity, targeting A549 lung adenocarcinoma via EGF inhibition","authors":"Hessa H. Al-Rasheed , Sarah A. Al-Khamis , Assem Barakat , Aliaa A. Masoud , Ahmed A. Sobhy , Doaa A. Ghareeb , Beatriz G. de la Torre , Fernando Albericio , Ayman El-Faham","doi":"10.1016/j.tet.2024.134424","DOIUrl":"10.1016/j.tet.2024.134424","url":null,"abstract":"<div><div>Merging <em>s</em>-triazine and isatin <em>via</em> a hydrazone linkage an efficient strategy to access new potential anticancer derivatives. Consequently, herein we report a new library of fifty new compounds based on isatin-<em>s</em>-triazine hydrazone derivatives. We used a straightforward orthogonal synthetic pathway to prepare disubstituted <em>s</em>-triazine hydrazine derivatives, whose basic structure was modified and then condensed with substituted isatin at the C-5 position to afford the new library of isatin-<em>s</em>-triazine hydrazone derivatives. The newly synthesized compounds were fully characterized by <sup>1</sup>H NMR, <sup>13</sup>C NMR and elemental analysis. The synthesized compounds were evaluated for their antiproliferative activity against lung cancer cell line (A549), and safety profile against Human Caucasian foetal lung (WI-38). The results revealed that all tested compounds exhibited cytotoxic effects against A549 when compared to the reference drug sorafenib. Most of the tested compounds exhibited safety indices that were either equivalent to or higher than sorafenib's index of 11.025, highlighting their superior or comparable safety profiles. Notably, compounds <strong>9a</strong>, <strong>9d</strong>, <strong>10d</strong>, <strong>13a</strong>, <strong>13d</strong>, <strong>14a-14e</strong>, <strong>15a</strong>, <strong>15b</strong>, <strong>15d</strong>, <strong>15e</strong>, and <strong>11a-11e</strong> exhibited particularly promising safety profiles. However, in terms of selectivity, compounds <strong>6a-6e</strong>, <strong>7a-7e, 8a-8e</strong>, <strong>10d</strong>, <strong>12d</strong>, <strong>13a</strong>, <strong>13d</strong>, <strong>14a</strong>, <strong>14d</strong> (with the highest selectivity index), <strong>11c</strong>, and <strong>11d</strong>, <strong>14e</strong>, <strong>15a</strong>, <strong>15b</strong>, <strong>15d</strong>, and <strong>15e</strong> showed greater potency than sorafenib, as evidenced by selectivity indices exceeding 1. In addition, all compounds demonstrated broad-spectrum anti-trypsin properties, five compounds (<strong>7c</strong>, <strong>8a</strong>, <strong>12d</strong>, <strong>13a</strong>, and <strong>13d</strong>) exhibited promising anti-trypsin effects at their anticancer IC<sub>50</sub> values (97.912 ± 12.14, 93.511 ± 10.32, 99.623 ± 14.71, 98.411 ± 25.3, and 75.123 ± 4.32, respectively), while <strong>7c</strong>, <strong>8a</strong>, <strong>12d</strong> and <strong>13a</strong> showed the highest inhibitory effect, surpassing the inhibitory effect of bis(5-amidino-2-benzimidazolyl)methane (IC<sub>50</sub> = 56.617 ± 2.14). When compared to the inhibitory effect of rivaroxaban (53.223 ± 0.98) at a concentration of 0.0013 μM against Factor Xa, all compounds showed lower inhibitory effects except for <strong>6b</strong>, <strong>6c</strong>, <strong>7a</strong>,<strong>7e</strong>, <strong>8a</strong>, <strong>8b</strong>, <strong>8c</strong>, <st","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"171 ","pages":"Article 134424"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143181113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tet.2024.134409
Shigeru Yonekubo, Motoyasu Ozawa, Chiaki Handa
1-(3-Fluoro-4-hydroxybenzyl)-5-hydroxy-2,3-dihydro-1H-indene-1-carbonitrile rac-1a is a potent and highly selective agonist for estrogen receptor β that shows potential as a therapeutic agent for obesity and depression in postmenopausal women. To assess the more precise pharmacological actions of rac-1a, a stable and large-scale supply of optically active (R)-1a is required. In this study, our objective was to synthesize (R)-1a by developing a rapid and more efficient asymmetric synthetic pathway. The rapid supply of (R)-1a was accomplished by diastereomeric resolution of the easily obtainable racemic precursor 1-(3-fluoro-4-methoxybenzyl)-5-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid rac-3a using a chiral oxazolidinone auxiliary. Despite the need to discard the unwanted enantiomer, this approach enabled stable gram-scale supply of (R)-1a by a short process that minimized purification by column chromatography. Furthermore, by exploring more efficient synthetic methods, we synthesized chiral precursor (R)-3a by asymmetric desymmetrization of 1,3-diol 5, which is an important reaction in asymmetric synthesis.
{"title":"Asymmetric synthesis of an optically active 1-benzylindane derivative as a selective agonist for estrogen receptor beta","authors":"Shigeru Yonekubo, Motoyasu Ozawa, Chiaki Handa","doi":"10.1016/j.tet.2024.134409","DOIUrl":"10.1016/j.tet.2024.134409","url":null,"abstract":"<div><div>1-(3-Fluoro-4-hydroxybenzyl)-5-hydroxy-2,3-dihydro-1<em>H</em>-indene-1-carbonitrile <em>rac</em>-<strong>1a</strong> is a potent and highly selective agonist for estrogen receptor β that shows potential as a therapeutic agent for obesity and depression in postmenopausal women. To assess the more precise pharmacological actions of <em>rac</em>-<strong>1a</strong>, a stable and large-scale supply of optically active (<em>R</em>)-<strong>1a</strong> is required. In this study, our objective was to synthesize (<em>R</em>)-<strong>1a</strong> by developing a rapid and more efficient asymmetric synthetic pathway. The rapid supply of (<em>R</em>)-<strong>1a</strong> was accomplished by diastereomeric resolution of the easily obtainable racemic precursor 1-(3-fluoro-4-methoxybenzyl)-5-methoxy-2,3-dihydro-1<em>H</em>-indene-1-carboxylic acid <em>rac</em>-<strong>3a</strong> using a chiral oxazolidinone auxiliary. Despite the need to discard the unwanted enantiomer, this approach enabled stable gram-scale supply of (<em>R</em>)-<strong>1a</strong> by a short process that minimized purification by column chromatography. Furthermore, by exploring more efficient synthetic methods, we synthesized chiral precursor (<em>R</em>)-<strong>3a</strong> by asymmetric desymmetrization of 1,3-diol <strong>5</strong>, which is an important reaction in asymmetric synthesis.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"171 ","pages":"Article 134409"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143181145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tet.2024.134387
Moustafa Hamaad, Rudolf J. Wehmschulte
Novel peptide-based tetracarboxylate ligands that consist of a pair of isophthalate moieties (ditopic 1,3-benzene dicarboxylate groups) bridged together through their 5-position by a flexible peptide core spacer have been synthesized through solution-phase peptide synthesis based on Boc chemistry (Boc: tert-butyloxycarbonyl). The peptide spacer component of the ligands is based on Glycine-Glycine, Alanine-Glycine, Phenylalanine-Glycine, Tryptophan-Glycine, Serine-Glycine, Aspartic-Glycine dipeptides and the Glycine-Glycine-Glycine tripeptide. These novel linkers are potential candidates as key building blocks for the construction of biomimetic metal-organic frameworks (MOFs).
{"title":"Synthesis of novel peptide-based tetracarboxylate ligands for metal organic framework (MOF) systems and applications","authors":"Moustafa Hamaad, Rudolf J. Wehmschulte","doi":"10.1016/j.tet.2024.134387","DOIUrl":"10.1016/j.tet.2024.134387","url":null,"abstract":"<div><div>Novel peptide-based tetracarboxylate ligands that consist of a pair of isophthalate moieties (ditopic 1,3-benzene dicarboxylate groups) bridged together through their 5-position by a flexible peptide core spacer have been synthesized through solution-phase peptide synthesis based on Boc chemistry (Boc: tert-butyloxycarbonyl). The peptide spacer component of the ligands is based on Glycine-Glycine, Alanine-Glycine, Phenylalanine-Glycine, Tryptophan-Glycine, Serine-Glycine, Aspartic-Glycine dipeptides and the Glycine-Glycine-Glycine tripeptide. These novel linkers are potential candidates as key building blocks for the construction of biomimetic metal-organic frameworks (MOFs).</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"171 ","pages":"Article 134387"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143181112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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