Design and synthesis of spiro derivatives of parthenin as novel anti-cancer agents
Several novel spiro derivatives of parthenin ( 1) have been synthesized by the dipolar cycloaddition using various dipoles viz; benzonitrile oxides, nitrones and azides with exocyclic double bond of C ring (α-methylene-γ-butyrolactone). Majority of the compounds exhibited improved anti-cancer activi...
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| Published in: | European journal of medicinal chemistry Vol. 46; no. 8; pp. 3210 - 3217 |
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| Main Authors: | , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Kidlington
Elsevier Masson SAS
01-08-2011
Elsevier |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Several novel spiro derivatives of parthenin (
1) have been synthesized by the dipolar cycloaddition using various dipoles
viz; benzonitrile oxides, nitrones and azides with exocyclic double bond of C ring (α-methylene-γ-butyrolactone). Majority of the compounds exhibited improved anti-cancer activity compared to the parthenin, when screened for their
in vitro cytotoxicity against three human cancer cell lines
viz., SW-620, DU-145 and PC-3.
In vivo screening of select analog revealed improved anti-cancer activity with low mammalian toxicity as compared to parthenin. The results of the cytotoxicity pattern of these derivatives reveals the SAR of these sesquiterpinoid lactones and possible role of α,β-unsaturated ketone of parthenin in inhibiting NF-kB. A mechanistic correlation of anti-cancer activity along with
in vivo and western blotting experiments has been described.
Novel spiro derivatives of parthenin exhibited improved cytotoxicity as revealed by
in vitro screening and
in vivo testing of select analogs exhibited better anti-cancer activity with least mammalian toxicity as compared to parthenin.
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► Several novel spiro derivatives of parthenin have been synthesized by the dipolar cycloaddition using various dipoles
viz; benzonitrile oxides, nitrones and azides with exocyclic double bond of C ring (α-methylene-γ-butyrolactone). A focused library of 60 spiro analogs of parthenins encompassing isoxazolines, isoxazolidine and aziridine ring functionalities have been synthesized and screened for anti-cancer activity. ► Both
in vitro (cell based) and
in vivo anti-cancer activity data has been generated. Majority of the compounds exhibited improved anti-cancer activity compared to the parthenin, when screened for their
in vitro cytotoxicity against three human cancer cell lines
viz., SW-620, DU-145 and PC-3.
In vivo screening of select analog revealed improved anti-cancer activity with low mammalian toxicity as compared to parthenin. ► The results of the cytotoxicity pattern of these derivatives reveals the SAR of these sesquiterpinoid lactones and possible role of alpha, beta-unsaturated ketone of parthenin in inhibiting NF-kB. A mechanistic correlation of anti-cancer activity along with
in vivo and western blotting experiments has been described. ► SAR of parthenin could be established with clarity as it has been established through the present study that conservation of α,β-unsaturated ketonic moiety of parthenin is crucial for retaining the anti-cancer activity of the ligand whereas the modification of the α-methylene-γ-butyrolactone would facilitate better protein modulation thus enabling improved activity and bioavailability through fine tuning of hydrophilic lipophilic balance. ► The exocyclic double bond can be advantageously utilized to incorporate appropriate structural entities that may enhance the cytotoxicity of the parent molecule. |
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| ISSN: | 0223-5234 1768-3254 |
| DOI: | 10.1016/j.ejmech.2011.04.030 |