Design and synthesis of hepatoselective, pyrrole-based HMG-CoA reductase inhibitors

Pfefferkorn, Jeffrey A.; Song, Yuntao; Sun, Kuai Lin; Miller, Steven R.; Trivedi, Bharat K.; Choi, Chulho; Sorenson, Roderick J.; Bratton, Larry; Unangst, Paul C.; Larsen, Scott D.; Poel, Toni J.; Cheng, Xue Min; Lee, Chitase; Erasga, Noe; Auerbach, Bruce J.; Askew, Valerie; Dillon, Lisa; Hanselman, Jeffrey C.; Lin, Zhiwu; Lu, Gina H.; Robertson, Andrew W.; Olsen, Karl; Mertz, Thomas; Sekerke, Catherine; Pavlovsky, A.G.; Harris, Melissa S.; Bainbridge, G.R.; Caspers, Nicole; Chen, Huifen; Eberstadt, Matthias

doi:10.1016/j.bmcl.2007.05.096

Cited by 50 publications

(35 citation statements)

References 32 publications

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“…Lipophilicity of statins improves drug access to different tissues [17]. The more lipophilic statins achieve higher levels of exposure in non-hepatic tissues, while the hydrophilic statins are more hepatoselective [18, 19]. Thus, a differential effect of statins can be predicted among hepatic and non-hepatic tissues.…”

Section: Introductionmentioning

confidence: 99%

Lipophilic but not hydrophilic statins selectively induce cell death in gynecological cancers expressing high levels of HMGCoA reductase.

Kato

Smalley

Sadarangani

et al. 2009

Journal of Cellular and Molecular Medicine

107

114

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Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose- and time-dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase-8 and -9; BID cleavage, cytochrome C release and PARP cleavage. Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies.

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Section: Introductionmentioning

confidence: 99%

Lipophilic but not hydrophilic statins selectively induce cell death in gynecological cancers expressing high levels of HMGCoA reductase.

Kato

Smalley

Sadarangani

et al. 2009

Journal of Cellular and Molecular Medicine

107

114

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“…A treatment of 242 in water with 5% aqueous HCl solution for 24 h at 23 C to 25 C provided the ethyl ester 243, which was hydrolyzed with 10% aqueous NaOH solution in 3 h. The treatment of the sodium salt of pitavastatin that was formed with aqueous CaCl 2 solution precipitated pitavastatin calcium 244, which was collected after 1 h stirring at ambient temperature, to provide 84% yield of 244 at 99.8 area% HPLC purity.…”

Section: Assembly Of Pitavastatinmentioning

confidence: 99%

“…These studies have been focused on modifications to the heterocyclic cores of the known super-statins, while the 3,5-dihydroxyheptanoic/heptenoic acid moiety has generally remained unaltered [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. Based on its overall favorable safety profile and efficiency in comparison to the other super-statins, a modification of the atorvastatin pyrrole heterocyclic core has been studied extensively in this context.…”

Section: Hepatoselective Super-statinsmentioning

confidence: 99%

Recent Progress in the Synthesis of Super-Statins

Časar

2015

Topics in Heterocyclic Chemistry

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Super-statins now represent a mature class of marketed drugs that faces the patent cliff, as has already occurred for fluvastatin and atorvastatin and is approaching for rosuvastatin and pitavastatin. However, they continue to trigger huge scientific interest in terms of their efficient preparation. This is not surprising, as easier accessibility of super-statins will promote even bigger demand in the market and consequently the need for higher rates of the production and productivity. Therefore, the stimulus for the development of even more efficient synthetic approaches to the heterocyclic moieties of super-statins and their chiral lateralchain precursors is at a peak, as also for the assembly of the these two parts into super-statins. The present report summarizes recent developments in the field of the synthesis of super-statins published from 2010 to 2015. Emphasis is given to the analysis of novel approaches to the formation of the chiral statin lateral chain, with detailed discussion of the development of new routes to respective heterocyclic cores and the assembly of these key units into the final super-statin structure.

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“…[11][12][13] Structural variation of the heterocyclic rings through the manipulation of the heterocyclic core influences the activity of the resulting fused systemes, among these of pyrroles and their fused deivatives. [14][15][16] Due to their pharmaceutical importance, [17][18][19][20][21][22] attention was paid to develop a new synthetic route for pyrroles and their fused forms. [23][24][25][26][27][28] Pyrrolylacetic acid derivatives such as tolmetin (Rumatol ® ) and zomepirac (Zomax ® ) were proved to be NSAIDs 6 with strong anti-inflammatory activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Structure Activity Relationship of Some Indole Derivatives as Potential Anti-inflammatory Agents

Fatahala

Khedr

Mohamed

2017

ACSi

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A series of fused pyrroles were synthesized and tested for their in vivo anti-inflammatory activity. Among 14 examined derivatives, 5 derivatives (1b-e, g and 5b), showed a promising anti-inflammatory activity equivalent to reference anti-inflammatory drugs (indomethacin and ibuprofen). A molecular docking study was conducted to interpret the biological activities of the tested compounds. The docking results were complementary with the phase of the biological survey and confirmed the biological effects.

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Design and synthesis of hepatoselective, pyrrole-based HMG-CoA reductase inhibitors

Cited by 50 publications

References 32 publications

Lipophilic but not hydrophilic statins selectively induce cell death in gynecological cancers expressing high levels of HMGCoA reductase.

Lipophilic but not hydrophilic statins selectively induce cell death in gynecological cancers expressing high levels of HMGCoA reductase.

Recent Progress in the Synthesis of Super-Statins

Synthesis and Structure Activity Relationship of Some Indole Derivatives as Potential Anti-inflammatory Agents

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