Synthesis and comparative evaluation of 4-oxa- and 4-aza-podophyllotoxins as antiproliferative microtubule destabilizing agents

Чернышева, Н. Б.; Tsyganov, Dmitry V.; Philchenkov, Alex; Zavelevich, M P; Kiselyov, Alex S.; Semenov, Roman V.; Semenova, Marina N.; Семенов, В. В.

doi:10.1016/j.bmcl.2012.01.128

Cited by 28 publications

(23 citation statements)

References 30 publications

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“…The IC 50 values were also determined for podophyllotoxin and compared to those found elsewhere. It was found that the IC 50 value for podophyllotoxin against the Jurkat cells was 12±1 nM, which was also determined by Chernysheva et al at 10 nM (Chernysheva et al , 2012); and the IC 50 value against the HeLa cells was 25±5 nM, whereas Jordan et al reported the IC 50 of 20 nM (Jordan et al , 1992). In both cell lines, the treatment with the prodrug-loaded liposomes resulted in apoptosis mediated cancer cell death.…”

Section: Resultsmentioning

confidence: 64%

Lipophilic prodrug conjugates allow facile and rapid synthesis of high-loading capacity liposomes without the need for post-assembly purification

Mikhalin

Evdokimov

Frolova

et al. 2014

Journal of Liposome Research

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Dihydropyridopyrazoles are simplified synthetic analogues of podophyllotoxin that can effectively mimic its molecular scaffold and act as potent mitotic spindle poisons in dividing cancer cells. However, despite nanomolar potencies and ease of synthetic preparation, further clinical development of these promising anticancer agents is hampered due to their poor aqueous solubility. In this paper, we developed a prodrug strategy that enables incorporation of dihydropyridopyrazoles into liposome bilayers to overcome the solubility issues. The active drug was covalently connected to either myristic or palmitic acid anchor via carboxylesterase hydrolyzable linkage. The resulting prodrugs were self assembled into liposome bilayers from hydrated lipid films using ultrasound without the need for post-assembly purification. The average particle size of the prodrug-loaded liposomes was about 90 nm. The prodrug incorporation was verified by differential scanning calorimetry, spectrophotometry and gel filtration reaching maximum at 0.3 and 0.35 prodrug/lipid molar ratios for myristic and palmitic conjugates, respectively. However, the ratio of 0.2 was used in the particle size and biological activity experiments to maintain long-term stability of the prodrug-loaded liposomes against phase separation during storage. Antiproliferative activity was tested against HeLa and Jurkat cancer cell lines in vitro showing that the liposomal prodrug retained antitubulin activity of the parent drug and induced apoptosis mediated cancer cell death. Overall, the established data provide a powerful platform for further clinical development of dihydropyridopyrazoles using liposomes as the drug delivery system.

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Section: Resultsmentioning

confidence: 64%

Lipophilic prodrug conjugates allow facile and rapid synthesis of high-loading capacity liposomes without the need for post-assembly purification

Mikhalin

Evdokimov

Frolova

et al. 2014

Journal of Liposome Research

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“…Compared with 60 (IC 50 =7140 n m ), compound 131 a exhibited a stronger cytotoxic activity (IC 50 =2.71 n m ) against A549 cells. Compound 135 e showed a significant activity against A549 and Jurkat cell lines with IC 50 values of 15.14 and 17.5 n m , respectively …”

Section: Total Synthesis Of Podophyllotoxin and Its Analoguesmentioning

confidence: 99%

“… Synthesis of 4‐aza‐2,3‐didehydropodophyllotoxin analogues 129 – 141 . (a) benzene/AcOH, reflux, 8 h, then p ‐chloranil, CF 3 CO 2 H, r.t., 24 h; (b) AcOH/NaBH 3 CN, r.t., 15 h.…”

Section: Total Synthesis Of Podophyllotoxin and Its Analoguesmentioning

confidence: 99%

Recent Advances in the Chemistry and Biology of Podophyllotoxins

Xiang

Che

2017

Chemistry A European J

173

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Podophyllotoxin and its related aryltetralin cyclolignans belong to a family of important products that exhibit various biological properties (e.g., cytotoxic, insecticidal, antifungal, antiviral, anti-inflammatory, neurotoxic, immunosuppressive, antirheumatic, antioxidative, antispasmogenic, and hypolipidemic activities). This Review provides a survey of podophyllotoxin and its analogues isolated from plants. In particular, recent developments in the elegant total chemical synthesis, structural modifications, biosynthesis, and biotransformation of podophyllotoxin and its analogues are summarized. Moreover, a deoxypodophyllotoxin-based chemosensor for selective detection of mercury ion is described. In addition to the most active podophyllotoxin derivatives in each series against human cancer cell lines and insect pests listed in the tables, the structure-activity relationships of podophyllotoxin derivatives as cytotoxic and insecticidal agents are also outlined. Future prospects and further developments in this area are covered at the end of the Review. We believe that this Review will provide necessary information for synthetic, medicinal, and pesticidal chemistry researchers who are interested in the chemistry and biology of podophyllotoxins.

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“…It shows strong cytotoxic activity against a broad‐spectrum of cancer cell lines at the cellular level, and is effective in the treatment of wilms tumors, various genital tumors, non‐Hodgkin's lymphomas, and lung cancer (Imbert, ; Subrahmanyam et al., ; Utsugi et al., ). Etoposide, teniposide, and etopophos are used clinically for the treatment of various types of malignancies (Chernysheva et al., ; Kamal et al., ; Reddy, Srinivas, Chashoo, Saxena, & Kumar, ), especially for the small‐cell lung cancer, non‐Hodgkin's lymphoma, testicular carcinoma, leukemia, and kaposi's sarcoma (Duca et al., ). However, their clinical use has encountered certain limitations such as metabolic inactivation, development of drug resistance, and certain toxic effects (Kobayashi & Ratain, ).…”

Section: Introductionmentioning

confidence: 99%

Click chemistry‐based synthesis and cytotoxic activity evaluation of 4α‐triazole acetate podophyllotoxin derivatives

Hou

Zhang

Luo³

et al. 2018

Chem Biol Drug Des

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A series of novel 4α‐triazole acetate podophyllotoxin derivatives were synthesized via click chemistry. In vitro cytotoxic activity evaluation showed that most of the derivatives exhibited potent inhibitory activities against the tested cancer cell lines with low nanomolar IC50 values. Further studies demonstrated that compound 31 exhibited broad‐spectrum cytotoxic activities, effectively overcame drug‐resistance, and showed relatively weak cytotoxicity on non‐cancer cells. Preliminary mechanistic studies indicated that 31 might have action on microtubule, cause cell cycle arrest at G2/M phase, and induce apoptosis in human PC‐3 cancer cells.

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Synthesis and comparative evaluation of 4-oxa- and 4-aza-podophyllotoxins as antiproliferative microtubule destabilizing agents

Cited by 28 publications

References 30 publications

Lipophilic prodrug conjugates allow facile and rapid synthesis of high-loading capacity liposomes without the need for post-assembly purification

Lipophilic prodrug conjugates allow facile and rapid synthesis of high-loading capacity liposomes without the need for post-assembly purification

Recent Advances in the Chemistry and Biology of Podophyllotoxins

Click chemistry‐based synthesis and cytotoxic activity evaluation of 4α‐triazole acetate podophyllotoxin derivatives

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