Design, semi-synthesis and bioactivity evaluation of novel podophyllotoxin derivatives as potent anti-tumor agents

Sun, Wenxue; Sun, Fenjin; Meng, Junjun; Cao, Xiaohua; Zhao, Shiyuan; Wang, Changshui; Li, Luning; Jiang, Pei

doi:10.1016/j.bioorg.2022.105906

Cited by 10 publications

(7 citation statements)

References 39 publications

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“…13 C NMR (125 MHz, DMSO-d 6 ) δ 12.87, 13.46 (2CH 3 ), 34.50, 35.21 (2CH 2 ), 63.68, 64.57 (C-3a, C-9a), 121.89 (C-6), 123.91 (q, J = 272. 4 Hz, CF 3 ), 126.05 (q, J = 3.7 Hz, Ar-3,5), 129.04 (Ar-1), 129.59 (q, J = 32.1 Hz, Ar-2,6), 130.35 (CH), 137.25 (Ar-4), 148.07 (4a-CN), 157.81 (2-CO), 160.71 (7-CO). 19 1 H NMR (300 MHz, DMSO-d 6 ): δ 0.96 (t, 3H, J = 7.1 Hz, CH 3 ), 1.14 (t, J = 7.2 Hz, 3H, CH 3 ), 3.06-3.18 (m, 3H, NCH 2 ), 3.31-3.36 (m, 1H, NCH 2 ), 4.90 (dd, J = 6.1, 1.9 Hz, 1H, 9a-H), 4.97 (d, J = 6.0 Hz, 1H, 3a-H), 6.90 (d, J = 1.6 Hz, 1H, 4.1.2 General procedure for the synthesis of compounds 2a-2t.…”

Section: Chemistrymentioning

confidence: 99%

“…2,3 Tubulin proteins are well-verified targets for anticancer therapy. [4][5][6][7][8][9][10] Microtubules consisting of tubulin polymers are involved in cell growth, division, motility, and intracellular transport. [10][11][12][13] Microtubule-targeting agents interfere with tubulin polymerization/depolymerization processes, disrupt the process of cell division, evoke cell cycle arrest, and eventually lead to cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Recognition of arylmethylidene derivatives of imidazothiazolotriazinones as novel tubulin polymerization inhibitors

Izmest'ev,

Svirshchevskaya,

Akopov

et al. 2024

RSC Med. Chem.

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Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recognition of arylmethylidene derivatives of imidazothiazolotriazinones as novel tubulin polymerization inhibitors

Izmest'ev,

Svirshchevskaya,

Akopov

et al. 2024

RSC Med. Chem.

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“…Sun and colleagues synthesized 18 podophyllotoxin-β-aroylacrylic-related acids ( 135a – m , Scheme 35 ) [ 169 ]. β-Aroylacrylic acids can be considered a structural combination of chalcones and cinnamic acids, two naturally occurring aromatic compounds that exert a broad spectrum of pharmacological activities that are mostly dependent on the position of the substituent groups [ 170 , 171 ].…”

Section: C-ring Modifications Of the Podophyllotoxin Skeletonmentioning

confidence: 99%

“…In addition, this compound could arrest the cell cycle of HGC-27 cells in the G2/M phase caused by the upregulation of CDK1 protein expression and the downregulation of cyclin B1 and CDC25C. Apoptosis was also induced by compound 135l in HGC-27 cells in a time-dependent manner through the mitochondrial pathway [ 169 ].…”

Section: C-ring Modifications Of the Podophyllotoxin Skeletonmentioning

confidence: 99%

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile

Miranda-Vera,

Hernández,

García-García

et al. 2023

Pharmaceutics

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Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer agent, nevertheless, it has become a good lead compound for the synthesis of derivatives with fewer side effects and better selectivity. Several examples, such as etoposide, highlight the potential of this natural product for chemomodulation in the search for new antitumor agents. This review focuses on the recent chemical modifications (2017–mid-2023) of the podophyllotoxin skeleton performed mainly at the C-ring (but also at the lactone D-ring and at the trimethoxyphenyl E-ring) together with their biological properties. Special emphasis is placed on hybrids or conjugates with other natural products (either primary or secondary metabolites) and other molecules (heterocycles, benzoheterocycles, synthetic drugs, and other moieties) that contribute to improved podophyllotoxin bioactivity. In fact, hybridization has been a good strategy to design podophyllotoxin derivatives with enhanced bioactivity. The way in which the two components are joined (directly or through spacers) was also considered for the organization of this review. This comprehensive perspective is presented with the aim of guiding the medicinal chemistry community in the design of new podophyllotoxin-based drugs with improved anticancer properties.

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“…The rst batch of podophyllin antitumor drugs, such as etopophos, etoposide (VP-16) and teniposide (VM-26), were approved for marketing in Switzerland and the United States in the 1980s 11 . Due to the further development of novel epipodophyllotoxin antineoplastic drugs in the elds of medicine, biology, chemistry, and beyond, the demand for podophyllotoxin, its precursor substance podophyllotoxin, in the international market has been increasing 12,13 . Currently, the natural source of podophyllotoxin is primarily derived from S. hexandrum and some other Epipodophyllaceae plants 3,14 .S.…”

Section: Introductionmentioning

confidence: 99%

Cloning and bioinformatics analysis of key gene ShOMT3 of podophyllotoxin biosynthesis pathway in Sinopodophyllum hexandrum

Gao,

Zhao,

et al. 2024

Preprint

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Sinopodophyllum hexandrum (S. hexandrum) is an endangered traditional Chinese medicine as abundant podophyllotoxin with powerful anticancer activity. In this study, the rootstalks of S. hexandrum from different geographical locations in China [S1 (Gansu) and S2 (Shaanxi)] were used as research materials to clone the key gene pluviatolide O-methyltransferase 3 (ShOMT3) in the podophyllotoxin biosynthetic pathway. Subsequently, bioinformatics analysis of the ShOMT3 gene and its encoded protein was subjected to bioinformatics analysis using various analysis software including ProtParam, Tmhmm Server 2.0, SubLoc, Signal-P 5.0, and Swiss-model. The results of the analysis revealed that the CDS region of the ShOMT3 gene is 1119 bp long, encoding 372 amino acids. The theoretical molecular weight of the ShOMT3 protein is 41.32784 kD, and the theoretical isoelectric point (pI) is 5.27. The instability coefficient of the protein is 46.05, the aliphatic index is 93.58, and the grand average of hydropathicity (GRAVY) is 0.037, indicating that it is an unstable hydrophobic protein. The protein does not contain transmembrane domains or signal peptides, indicating that it is a non-secreted protein. Secondary structure prediction results suggests that the protein consists of alpha helices, random coils, extended strands, and beta-turns. Tertiary structure prediction results suggests that the protein functions as a monomer. In the phylogenetic tree, the ShOMT3 protein has the highest homology with Podophyllum peltatum (P. peltatum). The successful cloning and bioinformatics analysis of the ShOMT3 gene provide theoretical basis and excellent genetic resources for the molecular regulatory mechanism analysis of the podophyllotoxin biosynthetic pathway and molecular breeding in S. hexandrum.

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Design, semi-synthesis and bioactivity evaluation of novel podophyllotoxin derivatives as potent anti-tumor agents

Cited by 10 publications

References 39 publications

Recognition of arylmethylidene derivatives of imidazothiazolotriazinones as novel tubulin polymerization inhibitors

Recognition of arylmethylidene derivatives of imidazothiazolotriazinones as novel tubulin polymerization inhibitors

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile

Cloning and bioinformatics analysis of key gene ShOMT3 of podophyllotoxin biosynthesis pathway in Sinopodophyllum hexandrum

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