4-Aza-2,3-dehydro-4-deoxypodophyllotoxins: simple aza-podophyllotoxin analogues possessing potent cytotoxicity

Hitotsuyanagi, Yukio; Fukuyo, Masamoto; Tsuda, Kyoko; Kobayashi, M.; Ozeki, Akira; Itokawa, Hideji; Takeya, Koichi

doi:10.1016/s0960-894x(99)00693-9

Cited by 76 publications

(69 citation statements)

References 11 publications

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“…The preparation of this group of compounds requires selective chemical manipulation of the two aromatic rings (B-and E-rings) of the podophyllotoxin scaffold. These molecules are readily prepared from anilines, benzaldehydes and tetronic acid or 2,3-cyclopentanedione in good to excellent yield and have also shown better cytotoxic activity [29].…”

Section: Preparation Of Ligandsmentioning

confidence: 99%

Applying linear interaction energy method for binding affinity calculations of podophyllotoxin analogues with tubulin using continuum solvent model and prediction of cytotoxic activity

Alam

Naik

2009

Journal of Molecular Graphics and Modelling

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Section: Preparation Of Ligandsmentioning

confidence: 99%

Applying linear interaction energy method for binding affinity calculations of podophyllotoxin analogues with tubulin using continuum solvent model and prediction of cytotoxic activity

Alam

Naik

2009

Journal of Molecular Graphics and Modelling

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“…It revealed that these entire ligands bind in tubulin protein with high affinity showed activity (pIC 50 ) in between -2.00 and 2.77 lM. A few azapodophyllotoxin analogues were proved to be more than twice as cytotoxic as natural podophyllotoxin [30]. Among aza-podophyllotoxin derivatives the best activity, was found for structure 142 (pIC 50 = 2.77 lM) with better Glide score (-10.85) within the library.…”

Section: Biological Significancementioning

confidence: 99%

“…The preparation of this group of compounds requires selective chemical manipulation of the two aromatic rings (B and Erings) of the podophyllotoxin scaffold. These molecules are readily prepared from anilines, benzaldehydes and tetronic acid or 2,3-cyclopentanedione in good to excellent yield and have also shown better cytotoxic activity [30].…”

Section: Virtual Library Designmentioning

confidence: 99%

“…Cytotoxic activity of these podophyllotoxin analogues (Sublib I-V) was generally evaluated using P-388 leukemia cells and were collected from different sources [30,34,35] and included in Tables 1, 2, 3, 4, and 5. It has been seen that the dihydroquinoline analogues (127-154) belonging to aza-podophyllotoxin (sublib-V) have significantly better activitives (pIC 50 in the range of -2.00-2.77 lM) compared to the other sublibraries (I-IV).…”

Section: Molecular Docking Of Podophyllotoxin and Its Analoguesmentioning

confidence: 99%

“…The Glide score and DG bind energy value of this group of compounds are not so good and thus seem to interact with the tubulin protein less efficiently. Aza-podophyllotoxin analogues were generally prepared by selective chemical modification of the two aromatic rings (ring B and E) of natural podophyllotoxin [30]. The Glide score among the ligands of these libraries vary in between -11.18 and -6.71 and the overall difference is also very small -5.07.…”

Section: Biological Significancementioning

confidence: 99%

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Molecular modelling evaluation of the cytotoxic activity of podophyllotoxin analogues

Alam

Naik

2008

J Comput Aided Mol Des

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Podophyllotoxin and its structural derivatives, a class of tubulin polymerization inhibitors, have been the objective of numerous studies to prepare better and safer anti-cancer drugs. A library of podophyllotoxin analogues has been designed consisting of 154 analogues. Their molecular interactions and binding affinities with tubulin protein (1SA1) have been studied using the docking-molecular mechanics based on generalized Born/surface area (MM-GBSA) solvation model. Quantitative structure activity relationships were developed between the cytotoxic activity (pIC(50)) of these compounds and molecular descriptors like docking score and binding free energy. For both the cases the r(2) was in the range of 0.642-0.728 indicating good data fit and r(cv)(2) was in the range of 0.631-0.719 indicating that the predictive capabilities of the models were acceptable. In addition, a linear correlation was observed between the predicted and experimented pIC(50) for the validation data set with correlation coefficient r(2) of 0.806 and 0.887, suggesting that the docked structure orientation and the interaction energies are reasonable. Low levels of root mean square error for the majority of inhibitors establish the docking and Prime/MM-GBSA based prediction model as an efficient tool for generating more potent and specific inhibitors of tubulin protein by testing rationally designed lead compounds based on podophyllotoxin derivatization.

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Organocatalytic Enantioselective Dearomatization Reactions for the Synthesis of Nitrogen Heterocycles

Phillips

2020

Synthetic Approaches to Nonaromatic Nitrogen Heterocycles

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4-Aza-2,3-dehydro-4-deoxypodophyllotoxins: simple aza-podophyllotoxin analogues possessing potent cytotoxicity

Cited by 76 publications

References 11 publications

Applying linear interaction energy method for binding affinity calculations of podophyllotoxin analogues with tubulin using continuum solvent model and prediction of cytotoxic activity

Applying linear interaction energy method for binding affinity calculations of podophyllotoxin analogues with tubulin using continuum solvent model and prediction of cytotoxic activity

Molecular modelling evaluation of the cytotoxic activity of podophyllotoxin analogues

Organocatalytic Enantioselective Dearomatization Reactions for the Synthesis of Nitrogen Heterocycles

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