Cyclopentanes are common substructures in biologically relevant molecules, but methods for their de novo synthesis from simple building blocks are limited. In this work, we report the development of a novel reagent that allows the direct transformation of ketones and aldehydes into an interesting cyclopentenone moiety. The reagent design hinges on a β-keto phosphonate incorporating a 1,4-dithiane-fused vinylketone. This sulfur heterocycle facilitates a one-pot Horner–Wadsworth–Emmons olefination followed by a Nazarov reaction of the resulting divinylketone.
{"title":"Development of a Carbonyl Cyclopentannulation Reagent Based on a 1,4-Dithiane-Fused Nazarov Reaction","authors":"Ellen Demeyere,Kristof Van Hecke,Johan M. Winne","doi":"10.1021/acs.joc.6c01924","DOIUrl":"https://doi.org/10.1021/acs.joc.6c01924","url":null,"abstract":"Cyclopentanes are common substructures in biologically relevant molecules, but methods for their de novo synthesis from simple building blocks are limited. In this work, we report the development of a novel reagent that allows the direct transformation of ketones and aldehydes into an interesting cyclopentenone moiety. The reagent design hinges on a β-keto phosphonate incorporating a 1,4-dithiane-fused vinylketone. This sulfur heterocycle facilitates a one-pot Horner–Wadsworth–Emmons olefination followed by a Nazarov reaction of the resulting divinylketone.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"82 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In this study, novel tricyclic compounds based on bispidine were prepared via a Michael addition–Henry domino reaction. This reaction sequence proceeds under mild conditions with high diastereoselectivity. Postsynthetic transformation pathways for the resulting nitro alcohols were demonstrated, leading to tricyclic amino alcohols of various structures.
{"title":"Conformational Lability of Bispidine as a Route to New Polycyclic Compounds","authors":"Aleksei V. Medved’ko,Sergey Z. Vatsadze","doi":"10.1021/acs.joc.6c01744","DOIUrl":"https://doi.org/10.1021/acs.joc.6c01744","url":null,"abstract":"In this study, novel tricyclic compounds based on bispidine were prepared via a Michael addition–Henry domino reaction. This reaction sequence proceeds under mild conditions with high diastereoselectivity. Postsynthetic transformation pathways for the resulting nitro alcohols were demonstrated, leading to tricyclic amino alcohols of various structures.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"12 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The divergent radical annulation reactions of ortho-cyanoaryl acrylamides involving cyanomethyl and α-oxyalkyl radicals were investigated using density functional theory (DFT) combined with DLPNO-CCSD(T) single-point computations. The calculations provide a detailed mechanistic comparison of the experimentally observed reaction pathways and reveal distinct downstream reactivity of the corresponding radical intermediates. Activation strain model (ASM) analyses show that the competing cyclization and C–C bond cleavage via β-scission pathways are characterized by different balances between structural distortion and interfragment interactions. For the cyanomethyl-radical-derived system, the cyclization pathway is associated with a substantially lower distortion energy, whereas for the α-oxyalkyl-radical-derived system, the cleavage pathway benefits from stronger stabilizing interfragment interactions that compensate for the larger distortion penalty. Noncovalent interaction (NCI) analyses provide qualitative structural support for these energetic trends. Overall, these computations provide a detailed mechanistic comparison of the competing downstream pathways of the cyanomethyl- and α-oxyalkyl-radical-derived intermediates.
{"title":"Deciphering the Mechanistic Origin of Divergent Radical Annulation Reactions of ortho-Cyanoaryl Acrylamides","authors":"Meryem Fıstıkçı,Yunus Zozik,Selçuk Eşsiz","doi":"10.1021/acs.joc.6c01863","DOIUrl":"https://doi.org/10.1021/acs.joc.6c01863","url":null,"abstract":"The divergent radical annulation reactions of ortho-cyanoaryl acrylamides involving cyanomethyl and α-oxyalkyl radicals were investigated using density functional theory (DFT) combined with DLPNO-CCSD(T) single-point computations. The calculations provide a detailed mechanistic comparison of the experimentally observed reaction pathways and reveal distinct downstream reactivity of the corresponding radical intermediates. Activation strain model (ASM) analyses show that the competing cyclization and C–C bond cleavage via β-scission pathways are characterized by different balances between structural distortion and interfragment interactions. For the cyanomethyl-radical-derived system, the cyclization pathway is associated with a substantially lower distortion energy, whereas for the α-oxyalkyl-radical-derived system, the cleavage pathway benefits from stronger stabilizing interfragment interactions that compensate for the larger distortion penalty. Noncovalent interaction (NCI) analyses provide qualitative structural support for these energetic trends. Overall, these computations provide a detailed mechanistic comparison of the competing downstream pathways of the cyanomethyl- and α-oxyalkyl-radical-derived intermediates.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"16 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The sodium borohydride (NaBH4) reduction of esters in toluene (also in 2-MeTHF and CPME) has been accomplished using 2-methoxyethanol (2-ME) as an activator. In previous mixed-solvent methods, it was necessary to add methanol dropwise to NaBH4 to suppress the formation of inactive species. In contrast, the present method enables the all-at-once addition of 2-ME. The most plausible active species is likely to be NaBH(OCH2CH2OCH3)3, and its reducing ability was assessed by DFT calculations.
{"title":"Sodium Borohydride Reduction of Esters in Toluene Using the All-at-Once Addition Method with an Alcohol Activator","authors":"Toshinobu Korenaga,Reito Endo,Mayu Ishida,Mizuki Nakagawa,Yuto Honma","doi":"10.1021/acs.joc.6c01934","DOIUrl":"https://doi.org/10.1021/acs.joc.6c01934","url":null,"abstract":"The sodium borohydride (NaBH4) reduction of esters in toluene (also in 2-MeTHF and CPME) has been accomplished using 2-methoxyethanol (2-ME) as an activator. In previous mixed-solvent methods, it was necessary to add methanol dropwise to NaBH4 to suppress the formation of inactive species. In contrast, the present method enables the all-at-once addition of 2-ME. The most plausible active species is likely to be NaBH(OCH2CH2OCH3)3, and its reducing ability was assessed by DFT calculations.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"37 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Naresh Gantasala,Narsihmulu Cheryala,Gunda I. Georg
We report a practical synthesis of the nonhormonal male contraceptive YCT-529. The method features key transformations: Grignard-mediated acetylation, the α-methylenation of a methyl ketone, and pyrrole formation via the Stetter and Paal–Knorr reaction sequence. It avoids iridium and palladium catalysts, overcoming the major limitations of an earlier synthesis. The current scalable synthesis proceeds in 6 steps from bromochromene 4 in 51% overall yield and does not require chromatographic purification.
{"title":"Second-Generation Synthesis of the Male Contraceptive YCT-529","authors":"Naresh Gantasala,Narsihmulu Cheryala,Gunda I. Georg","doi":"10.1021/acs.joc.6c01804","DOIUrl":"https://doi.org/10.1021/acs.joc.6c01804","url":null,"abstract":"We report a practical synthesis of the nonhormonal male contraceptive YCT-529. The method features key transformations: Grignard-mediated acetylation, the α-methylenation of a methyl ketone, and pyrrole formation via the Stetter and Paal–Knorr reaction sequence. It avoids iridium and palladium catalysts, overcoming the major limitations of an earlier synthesis. The current scalable synthesis proceeds in 6 steps from bromochromene 4 in 51% overall yield and does not require chromatographic purification.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"56 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mechanochemistry has emerged as a transformative innovation in chemical synthesis, enabling solvent-free, energy-efficient transformations that align with the principles of green chemistry. Herein, we report a sequential two-step, one-pot ball-milling protocol for the synthesis of 1,3,5-trisubstituted 1,2,4-triazoles, expanding the scope of nitrogen heterocycle chemistry into the mechanochemical domain. N-aroyl and acyl amidines were prepared quantitatively from benzamides, heteroaryl carboxamides, and alkyl carboxamides using 1,1-dimethoxy-N,N-dimethylmethan or ethanamine (DMF-DMA or DMA-DMA), or Bredereck’s reagent (tert-butoxy bis(dimethylamino)methane) under solvent-free milling conditions, followed by condensation with hydrazines in the presence of acetic acid to afford triazoles in good to excellent yields (51–91%). The methodology demonstrated broad substrate tolerance, including aryl, heteroaryl, and alkyl derivatives, and was successfully applied to the sustainable synthesis of penipanoid A, a bioactive marine natural product, under mild, solvent-free conditions.
机械化学已经成为化学合成的革命性创新，使无溶剂、节能的转化符合绿色化学的原则。在此，我们报道了一个连续的两步，一锅球磨工艺合成1,3,5-三取代1,2,4-三唑，将氮杂环化学的范围扩展到机械化学领域。用1,1-二甲氧基- n， n -二甲胺或乙胺（DMF-DMA或DMA-DMA）或Bredereck试剂（叔丁基二（二甲胺）甲烷）在无溶剂研磨条件下定量制备了苯酰胺、杂芳基羧酰胺和烷基羧酰胺，然后在乙酸存在下与肼缩合，得到了收率为51-91%的三唑。该方法具有广泛的底物耐受性，包括芳基、杂芳基和烷基衍生物，并成功应用于温和、无溶剂条件下可持续合成具有生物活性的海洋天然产物萜类化合物A。
{"title":"Mechanochemistry-Enabled One-Pot Formation of 1,2,4-Triazoles toward the Sustainable Penipanoid A Synthesis","authors":"Sachin Balu Chavan,Dipali Rao,Sushila Dilraj Joshi,Mangala Phadte","doi":"10.1021/acs.joc.6c02087","DOIUrl":"https://doi.org/10.1021/acs.joc.6c02087","url":null,"abstract":"Mechanochemistry has emerged as a transformative innovation in chemical synthesis, enabling solvent-free, energy-efficient transformations that align with the principles of green chemistry. Herein, we report a sequential two-step, one-pot ball-milling protocol for the synthesis of 1,3,5-trisubstituted 1,2,4-triazoles, expanding the scope of nitrogen heterocycle chemistry into the mechanochemical domain. N-aroyl and acyl amidines were prepared quantitatively from benzamides, heteroaryl carboxamides, and alkyl carboxamides using 1,1-dimethoxy-N,N-dimethylmethan or ethanamine (DMF-DMA or DMA-DMA), or Bredereck’s reagent (tert-butoxy bis(dimethylamino)methane) under solvent-free milling conditions, followed by condensation with hydrazines in the presence of acetic acid to afford triazoles in good to excellent yields (51–91%). The methodology demonstrated broad substrate tolerance, including aryl, heteroaryl, and alkyl derivatives, and was successfully applied to the sustainable synthesis of penipanoid A, a bioactive marine natural product, under mild, solvent-free conditions.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"234 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qin Luo,Yi-Ting Wang,Meng-Zhen Wei,Zhi-Bo Xie,Cong-Hai Zhang,Sheng-Jiao Yan
We report a Sc(OTf)3/AgOAc relay-catalyzed multicomponent [4 + 1] cycloaddition cascade for the efficient synthesis of polysubstituted pyrazoles 5–6 from sulfoxonium ylides, vinyl diazo esters, and vinylene carbonates or maleimides. Although vinyl diazo esters have been widely used as C1 and three-atom synthons, their application as four-atom (C2N2) building blocks remains underexplored. This bimetallic relay strategy features well-defined and complementary catalytic roles: Sc(III) promotes pyrazole ring assembly, whereas Ag(I) facilitates sequential alkene functionalization while suppressing undesired side reactions. The one-pot cascade proceeds under ambient conditions with excellent step economy, forms three new chemical bonds in a single operation, and affords structurally diverse pyrazoles with good functional-group tolerance. Mechanistic studies support the proposed relay catalytic pathway. The reaction is readily scalable to gram scale, providing a modular and practical approach to the rapid synthesis and late-stage diversification of biologically valuable pyrazole derivatives.
{"title":"Sequential Relay Catalysis in a Multicomponent [4 + 1] Cycloaddition for the Synthesis of Highly Functionalized Pyrazoles","authors":"Qin Luo,Yi-Ting Wang,Meng-Zhen Wei,Zhi-Bo Xie,Cong-Hai Zhang,Sheng-Jiao Yan","doi":"10.1021/acs.joc.6c01662","DOIUrl":"https://doi.org/10.1021/acs.joc.6c01662","url":null,"abstract":"We report a Sc(OTf)3/AgOAc relay-catalyzed multicomponent [4 + 1] cycloaddition cascade for the efficient synthesis of polysubstituted pyrazoles 5–6 from sulfoxonium ylides, vinyl diazo esters, and vinylene carbonates or maleimides. Although vinyl diazo esters have been widely used as C1 and three-atom synthons, their application as four-atom (C2N2) building blocks remains underexplored. This bimetallic relay strategy features well-defined and complementary catalytic roles: Sc(III) promotes pyrazole ring assembly, whereas Ag(I) facilitates sequential alkene functionalization while suppressing undesired side reactions. The one-pot cascade proceeds under ambient conditions with excellent step economy, forms three new chemical bonds in a single operation, and affords structurally diverse pyrazoles with good functional-group tolerance. Mechanistic studies support the proposed relay catalytic pathway. The reaction is readily scalable to gram scale, providing a modular and practical approach to the rapid synthesis and late-stage diversification of biologically valuable pyrazole derivatives.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"12 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An efficient visible-light photoredox-catalyzed Sp3 C-H sulfonylation protocol for the synthesis of β-keto sulfones has been developed. The utilization of Ir{dF(CF3)(ppy)2dtbpy}PF6 as the photocatalyst and blue LEDs as the light sources enabled the formation of alkyl carbon radical and sulfonyl radical species from oxime ester and sodium sulfinate, allowing the radical-radical cross-coupling process to form C-S bonds, following a subsequent hydrolysis to deliver the corresponding β-keto sulfones in moderate to excellent isolated yields.
{"title":"Visible-Light Photoredox-Catalyzed Sp3 C-H Sulfonylation of Oxime Ester.","authors":"Zijie Zhang, Yuejie Sun, Jie Huang, Yiqi Yan, Yujie Zhi, Ying Han, Shaoqun Zhu","doi":"10.1021/acs.joc.6c01729","DOIUrl":"https://doi.org/10.1021/acs.joc.6c01729","url":null,"abstract":"<p><p>An efficient visible-light photoredox-catalyzed Sp3 C-H sulfonylation protocol for the synthesis of β-keto sulfones has been developed. The utilization of Ir{dF(CF3)(ppy)2dtbpy}PF6 as the photocatalyst and blue LEDs as the light sources enabled the formation of alkyl carbon radical and sulfonyl radical species from oxime ester and sodium sulfinate, allowing the radical-radical cross-coupling process to form C-S bonds, following a subsequent hydrolysis to deliver the corresponding β-keto sulfones in moderate to excellent isolated yields.</p>","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zi-Teng Yang,Huifen Ma,Shi-Chao Li,Xu Guo,Xinling Wang,Jing Yang,Li-Xin Li
Herein, we have achieved the one-step synthesis of a series of o-carborane amide derivatives directly from o-carborane carboxylic acids using commercially available triphenylphosphine dibromide as the activating reagent. Mechanistic studies demonstrate that the strong bond-forming tendency and excellent leaving ability of the P–O bond effectively inhibit both the decarboxylation and the leaving tendency of the o-carborane unit.
{"title":"Synthesis of o-Carborane Amides from o-Carborane Carboxylic Acids via Acyloxyphosphonium Ion","authors":"Zi-Teng Yang,Huifen Ma,Shi-Chao Li,Xu Guo,Xinling Wang,Jing Yang,Li-Xin Li","doi":"10.1021/acs.joc.6c00728","DOIUrl":"https://doi.org/10.1021/acs.joc.6c00728","url":null,"abstract":"Herein, we have achieved the one-step synthesis of a series of o-carborane amide derivatives directly from o-carborane carboxylic acids using commercially available triphenylphosphine dibromide as the activating reagent. Mechanistic studies demonstrate that the strong bond-forming tendency and excellent leaving ability of the P–O bond effectively inhibit both the decarboxylation and the leaving tendency of the o-carborane unit.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"26 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rajat H. Sudarshana,Madhu Ramesh,Ramjayakumar Venkatesh,Krishna N. Ganesh
Peptide nucleic acids are neutral analogues of DNA with an aminoethyl glycine polyamide backbone, which renders a higher binding affinity to complementary DNA but reduces cell permeability due to increased hydrophobicity. We have conjugated aeg-PNA with the cationic amino acids lysine (lys), arginine (arg), and the dipeptides lys-lys and arg-arg at the N/C-terminus and introduced cationic S-aminomethylene (S-am) and S-methylene guanidine (S-mgd) side chains at Cα in 8-mer PNAs. The thermal stability of cationic PNA:DNA duplexes was enhanced due to electrostatic interactions between the cationic PNA substitutions and the anionic DNA in the range of 6–11 °C and in the following order: PNA 12-S-am2 >PNA 9-S-mgd >PNA 10-lys2 >PNA 5-S-mgd >PNA 4 S-am)∼PNA 8-arg>PNA 11-arg2, and the rest were < 3.0 °C. The side-chain-modified substitutions were generally better than the end-conjugated amino acids. The single-stranded C-terminus cationic PNAs showed 1.4–1.7-fold higher cell uptake than aeg-PNA in SH-SY5Y cells, in the following order: S-am2>S-mgd >arg2>lys> lys2>arg>S-am>aeg-PNA. FRET experiments of cationic PNA hybridized with fluorescently labeled DNA within cells exhibited increased cellular uptake of PNA:DNA duplexes, with the CF-PNA 12-S-am2 up by 12.7-fold, suggesting significantly improved cell uptake of cationic PNA:DNA duplexes. FRET imaging indicated the uptake of intact cationic PNA:DNA duplexes into the cells, suggesting their application potential for transporting DNA into cells.
{"title":"Conjugated and Side-Chain Cationic Peptide Nucleic Acids (PNAs): Synthesis and Enhanced Cell Uptake of Cationic PNAs and Their DNA Duplexes into Cells","authors":"Rajat H. Sudarshana,Madhu Ramesh,Ramjayakumar Venkatesh,Krishna N. Ganesh","doi":"10.1021/acs.joc.6c01245","DOIUrl":"https://doi.org/10.1021/acs.joc.6c01245","url":null,"abstract":"Peptide nucleic acids are neutral analogues of DNA with an aminoethyl glycine polyamide backbone, which renders a higher binding affinity to complementary DNA but reduces cell permeability due to increased hydrophobicity. We have conjugated aeg-PNA with the cationic amino acids lysine (lys), arginine (arg), and the dipeptides lys-lys and arg-arg at the N/C-terminus and introduced cationic S-aminomethylene (S-am) and S-methylene guanidine (S-mgd) side chains at Cα in 8-mer PNAs. The thermal stability of cationic PNA:DNA duplexes was enhanced due to electrostatic interactions between the cationic PNA substitutions and the anionic DNA in the range of 6–11 °C and in the following order: PNA 12-S-am2 >PNA 9-S-mgd >PNA 10-lys2 >PNA 5-S-mgd >PNA 4 S-am)∼PNA 8-arg>PNA 11-arg2, and the rest were < 3.0 °C. The side-chain-modified substitutions were generally better than the end-conjugated amino acids. The single-stranded C-terminus cationic PNAs showed 1.4–1.7-fold higher cell uptake than aeg-PNA in SH-SY5Y cells, in the following order: S-am2>S-mgd >arg2>lys> lys2>arg>S-am>aeg-PNA. FRET experiments of cationic PNA hybridized with fluorescently labeled DNA within cells exhibited increased cellular uptake of PNA:DNA duplexes, with the CF-PNA 12-S-am2 up by 12.7-fold, suggesting significantly improved cell uptake of cationic PNA:DNA duplexes. FRET imaging indicated the uptake of intact cationic PNA:DNA duplexes into the cells, suggesting their application potential for transporting DNA into cells.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"45 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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