-
Dong-Mei Zhang,
Ying-Jie Li,
Chang Shu,
Zhi-Xiong Ruan,
Wei-Min Chen,
Anita Yiu,
Ying-Hui Peng,
Jiao Wang, Ping Lan,
Zhe Yao,
Kwok-Pui Fung,
Li-Wu Fu,
Zhe-Sheng Chen,
Wen-Cai Ye
[show abstract]
[hide abstract]
ABSTRACT: Multidrug resistance (MDR) is a major obstacle to successful chemotherapy for cancer; thus, novel MDR reversers are urgently needed. In the present study, we assessed whether two synthetic derivatives of 23-hydroxybetulinic acid, 3,23-O-diacetyl-17-1,4'-bipiperidinyl betulinic amide (DABB) and 3,23-O-dihydroxy-17-1,4'-bipiperidinyl betulinic amide (DHBB), could reverse MDR induced by ATP-binding cassette (ABC) transporters. Using the MTT assay, we found that DABB and DHBB could enhance the cytotoxicities of ABCB1 substrates doxorubicin, vincristine, and paclitaxel in ABCB1-overexpressing HepG2/ADM and MCF-7/ADR cells, whereas that of a non-ABCB1 substrate cisplatin was unaffected. The ABCB1 substrate accumulation and efflux assay showed that DABB and DHBB not only enhanced the retention of doxorubicin and rhodamine123 but also inhibited the efflux of rhodamine123. Further mechanistic studies by reverse transcription PCR, western blot, and ABCB1 ATPase activity assay indicated that DABB and DHBB suppressed ABCB1 ATPase activity, but did not alter mRNA or protein expression of ABCB1. ABCB1 siRNA pretreatment attenuated the reversal effect of DABB and DHBB, indicating that their reversal effects were partially dependent on ABCB1. Docking analysis also implied that DABB and DHBB bind directly to ABCB1 at a site partly overlapped with that of verapamil. Taken together, our findings suggest that two bipiperidinyl derivatives of 23-hydroxybetulinic acid reverse ABCB1-mediated MDR through modulation of ABCB1 ATPase activity, thereby inhibiting its efflux function in both HepG2/ADM and MCF-7/ADR cells. These findings may contribute toward the development of novel MDR reversers using DABB and DHBB as adjuvant anticancer chemotherapy.
Anti-cancer drugs 03/2013; · 2.23 Impact Factor
-
Dong-Mei Zhang,
Chang Shu,
Jun-Jiang Chen,
Kamlesh Sodani,
Jiao Wang,
Jaya Bhatnagar, Ping Lan,
Zhi-Xiong Ruan,
Zhi-Jie Xiao,
Suresh V Ambudkar,
Wei-Min Chen,
Zhe-Sheng Chen,
Wen-Cai Ye
[show abstract]
[hide abstract]
ABSTRACT: 23-O-(1,4'-Bipiperidine-1-carbonyl)betulinic acid (BBA), a synthetic derivative of 23-hydroxybetulinic acid (23-HBA), shows a reversal effect on multidrug resistance (MDR) in our preliminary screening. Overexpression of ATP-binding cassette (ABC) transporters such as ABCB1, ABCG2, and ABCC1 has been reported in recent studies to be a major factor contributing to MDR. Our study results showed that BBA enhanced the cytotoxicity of ABCB1 substrates and increased the accumulation of doxorubicin or rhodamine123 in ABCB1 overexpressing cells, but had no effect on non ABCB1 substrate, such as cisplatin; what's more, BBA slightly reversed ABCG2-mediated resistance to SN-38, but did not affect the ABCC1-mediated MDR. Further studies on the mechanism indicated that BBA did not alter the expression of ABCB1 at mRNA or protein levels, but affected the ABCB1 ATPase activity by stimulating the basal activity at lower concentrations and inhibiting the activity at higher concentrations. In addition, BBA inhibited the verapamil-stimulated ABCB1 ATPase activity and the photolabeling of ABCB1 with [(125)I] iodoarylazidoprazosin in a concentration-dependent manner, indicating that BBA directly interacts with ABCB1. The docking study confirmed this notion that BBA could bind to the drug binding site(s) on ABCB1, but its binding position was only partially overlapping with that of verapamil or iodoarylazidoprazosin. Importantly, BBA increased the inhibitory effect of paclitaxel in ABCB1 overexpressing KB-C2 cell xenografts in nude mice. Taken together, our findings suggest that BBA can reverse ABCB1-mediated MDR by inhibiting its efflux function of ABCB1, which supports the development of BBA as a novel potential MDR reversal agent used in the clinic.
Molecular Pharmaceutics 10/2012; · 4.78 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 3D-QSAR studies were performed on a series of betulinic acid and betulin derivatives with anti-HIV-1 activities. 3D-QSAR models
of analysis A and analysis B, which were related to two activity indexes EC50 and TI, respectively, were built by using CoMFA and CoMSIA. The analysis A resulted from 41 molecules gave r
cv2 values of 0.664 and 0.718, r
2
values of 0.979 and 0.955, respectively. The analysis B also resulted from 41 molecules gave r
cv2 values of 0.570 and 0.559, r
2
values of 0.938 and 0.933, respectively. The contour maps generated from the two analyses provided the regions in space where
interactive fields may influence the activity. The results could serve as a useful guide for the design of potential betulinic
acid and betulin derivatives with better anti-HIV-1 activity.
Keywords3D-QSAR–CoMFA–CoMSIA–Betulinic acid–Betulin–Anti-HIV-1 activity
Medicinal Chemistry Research 04/2012; 20(8):1247-1259. · 1.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A set of 17 novel ketolides bearing an aryltetrazolyl-substituted alkyl side chain were synthesized and evaluated for their antibacterial activities, which the aryltetrazolyl group was selected to replace the hetero-aryl moiety of the side chain in telithromycin for designing new compounds. The synthesis of aryltetrazolyl alkylamines was reported in detail. The antibacterial activities of new ketolides were evaluated against a number of pathogens including macrolide-resistant organisms by using telithromycin as the reference. Many of the evaluated compounds exhibited remarkable activities against both erythromycin-susceptible and erythromycin-resistant organisms such as Staphylococcus aureus (except S. aureus AD-08), Pseudomonas aeruginosa and Escherichia coli. Among these, the compound 11e exhibited excellent antibacterial potency against all the strains in comparison with others.Keywords: antibacterial activity; aryltetrazolyl; ketolides; synthesis
The Journal of Antibiotics 07/2011; 64(8):571-581. · 1.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Presently, an in silico modeling was carried out on a series of 63 phosphonic acid-containing thiazole derivatives as fructose-1,6-bisphosphatase (FBPase) inhibitors using CoMFA/CoMSIA and molecular docking methods. The CoMFA and CoMSIA models using 51 molecules in the training set gave r (cv) (2) values of 0.675 and 0.619, r ( 2 ) values of 0.985 and 0.979, respectively. The systemic external validation indicated that our CoMFA and CoMSIA models possessed high predictive powers with r (0) (2) values of 0.995 and 0.994, r (m(test)) (2) values of 0.887 and 0.860, respectively. The 3D contour maps of the CoMFA and CoMSIA provided smooth and interpretable explanation of the structure-activity relationship for the inhibitors. Molecular docking studies revealed that a phosphonic group was essential for binding to the AMP binding site, and some key features were also identified. The analyses of the 3D contour plots and molecular docking results permitted interesting conclusions about the effects of different substituent groups at different positions of the common scaffold, which might guide the design of novel FBPase inhibitors with higher activity and bioavailability. A set of 60 new analogues were designed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models. The findings can be quite useful to aid the designing of new fructose-1,6-biphophatase inhibitors with improved biological response.
Journal of Molecular Modeling 06/2011; 18(3):973-90. · 1.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Chemotypes comprising the d-annulated 1,3-dihydro-2H-1-benzazepin-2-one scaffold derived from the paullone structure were found to be potent vascular endothelial growth factor receptor 2 (VEGF-R2) kinase inhibitors. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking studies were performed on a series of d-annulated benzazepinones with VEGF-R2 kinase inhibition activities. The comparative molecular field analysis and comparative molecular similarity indices analysis models using 32 molecules in the training set gave r(2)(cv) values of 0.811 and 0.769, r(2) values of 0.962 and 0.953, respectively. 3D contour maps generated from the two models revealed that the electron-withdrawing groups at R(1) and the bulky, electron-withdrawing as well as hydrogen bond donor groups at R(2) position are favourable; the bulky, hydrogen bond acceptor substituent at R(3) and the minor groups at R(4) position may benefit the potency. We have designed a series of novel VEGF-R2 inhibitors by utilizing the SAR results revealed in the present study, which were predicted with excellent potencies in the developed models. The results may aid in designing of potential VEGF-R2 inhibitors with better activities.
Journal of Enzyme Inhibition and Medicinal Chemistry 06/2011; 26(3):367-77. · 1.62 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Based on structural modifications of the natural 23-hydroxybetulinic acid, a series of novel its derivatives had been synthesized. The new compounds were screened for in vitro antiproliferative activity against cancer cell lines HeLa, MCF-7, HepG2, B16 and A375 using doxorubicin as a reference. The vast majority of derivatives had exhibited potent tumor growth inhibitory activity than original compound. The derivatives 4, 5, 7, 20, 23, 26, 43 and 44 with IC50 values lower than 10 μM on all tested cell lines were regarded as the most promising compounds. The structure-activity relationships of 23-hydroxybetulinic acid derivatives were also discussed in the present investigations.
European journal of medicinal chemistry 06/2011; 46(6):2490-502. · 3.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The Aurora kinases have been regarded as attractive targets for the development of new anticancer agents. Recently a series of azaindole derivatives with Aurora B inhibitory activities were reported. To explore the relationship between the structures of substituted azaindole derivatives and their inhibition of Aurora B, 3D-QSAR and molecular docking studies were performed on a dataset of 41 compounds. 3D-QSAR, including CoMFA and CoMSIA, were applied to identify the key structures impacting their inhibitory potencies. The CoMSIA model showed better results than CoMFA, with r(2)(cv) value of 0.575 and r(2) value of 0.987. 3D contour maps generated from CoMFA and CoMSIA along with the docking binding structures provided enough information about the structural requirements for better activity. Based on the structure-activity relationship revealed by the present study, we have designed a set of novel Aurora B inhibitors that showed excellent potencies in the developed models. Thus, our results allowed us to design new derivatives with desired activities.
Journal of Molecular Modeling 05/2011; 17(5):1191-205. · 1.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The pyrrolopyrimidine derivatives have been regarded as a novel class of LIM-kinase 2 inhibitor. To explore the relationship between the structures of substituted pyrrolopyrimidine derivatives and their inhibitory activities against LIMK2, CoMFA and CoMSIA analyses, and molecular docking studies were performed on a dataset of forty-one compounds. The two 3D-QSAR models resulted from thirty-one molecules in the training set gave r2 cv values of 0.635 and 0.660, r2 values of 0.973 and 0.965, respectively. The predictive ability of CoMFA and CoMSIA, determined using a test set of ten compounds, gave predictive correlation coefficients of 0.971 and 0.964, respectively. 3D contour maps generated from CoMFA and CoMSIA along with the docking binding structures provided enough information about the structural requirements for better activity. The results can serve as a useful guideline to design novel LIMK2 inhibitors with better potencies.
Letters in Drug Design & Discovery 02/2011; 8(3):229-240. · 0.87 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 3D-QSAR and docking studies were performed on sixty imidazo[4,5-b]pyridine derivatives as Aurora A kinase inhibitors. The CoMFA and CoMSIA models using forthy-eight molecules in the training set, gave r(cv)(2) values of 0.774 and 0.800, r(2) values of 0.975 and 0.977, respectively. The external validation indicated that both CoMFA and CoMSIA models possessed high predictive powers with r(pred)(2) values of 0.933 and 0.959, r(m)(2) values of 0.883 and 0.915, respectively. 3D contour maps generated from the two models along with docking binding structures have identified several key structural requirements responsible for the activity. A set of thirty new analogues were proposed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models.
European journal of medicinal chemistry 01/2011; 46(1):77-94. · 3.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 3D-QSAR and docking studies were performed on a series of pyrazolo[4,3-h]quinazoline-3-carboxamides as CDK2/CyA inhibitors. The CoMFA and CoMSIA models using 54 molecules in the training set, gave r(cv)(2) values of 0.644 and 0.507, r(2) values of 0.959 and 0.951, respectively. 3D contour maps generated from the two models were applied to identify features important for the activity and better understand the interaction between the inhibitors and the receptor. Molecular docking was employed to explore the binding mode between these compounds and the receptor, as well as help understanding the structure-activity relationship revealed by CoMFA and CoMSIA. The results provide a useful guideline for the rational design of novel CDKs inhibitors.
Bioorganic & medicinal chemistry letters 11/2010; 20(22):6764-72. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Betulinic acids are lupine-type pentacyclic triterpenoid saponins commonly found in some plants of Betulaceae family, especially in the bark of betula alba (birch). The potent anti-HIV and anti-tumor activities of betulinic acids have been greatly concerned. The natural betulinic acids include betulinic acid, 23-hydroxy betulinic acid, betulin and so on. Some investigations on the structural modifications of betulinic acids were carried out, and many derivatives with excellent biological activity have been obtained nowadays. In this paper, the research advances of the structural modification of betulinic acids, as well as their anti-HIV and anti-tumor activities are reviewed.
Yao xue xue bao = Acta pharmaceutica Sinica 11/2010; 45(11):1339-45.
-
[show abstract]
[hide abstract]
ABSTRACT: Fructose-1,6-biphophatase has been regarded as a novel therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). 3D-QSAR and docking studies were performed on a series of [5-(4-amino-1H-benzoimidazol-2-yl)-furan-2-yl]-phosphonic acid derivatives as fructose-1,6-biphophatase inhibitors. The CoMFA and CoMSIA models using thirty-seven molecules in the training set gave r (cv) (2) values of 0.614 and 0.598, r (2) values of 0.950 and 0.928, respectively. The external validation indicated that our CoMFA and CoMSIA models possessed high predictive powers with r (0) (2) values of 0.994 and 0.994, r (m) (2) values of 0.751 and 0.690, respectively. Molecular docking studies revealed that a phosphonic group was essential for binding to the receptor, and some key features were also identified. A set of forty new analogues were designed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models. The findings can be quite useful to aid the designing of new fructose-1,6-biphophatase inhibitors with improved biological response.
Journal of Computer-Aided Molecular Design 10/2010; 24(12):993-1008. · 3.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Novel anti-HIV-1 agents derived from betulinic acid have been greatly concerned. 3D-QSAR and molecular docking studies were applied to rationalize the structural requirements responsible for the anti-HIV activity of these compounds. The CoMFA and CoMSIA models resulted from 28 molecules gave r(cv)² values of 0.599 and 0.630, r² values of 0.994 and 0.958, respectively. To estimate the predictive ability of the 3D-QSAR model, an external validation was employed. Based on the contour maps generated from both CoMFA and CoMSIA, we have identified some key features in the betulinic acid derivatives that are responsible for the anti-HIV activity. Molecular docking was used to explore the binding mode between these derivatives and HIV gp120. We have therefore designed a series of novel betulinic acid derivatives by utilizing the SAR results revealed in the present study, which were predicted with excellent potencies in the developed models. The results provide a valuable method to design new betulinic acid derivatives as anti-HIV-1 agents.
Journal of Molecular Modeling 10/2010; 17(7):1643-59. · 1.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A series of C-12 pyrazolinyl spiro ketolide derivatives were designed and synthesized. The C-12 modifications involved replacing the natural C-12 methyl group in clarithromycin core with different pyrazolinyl spiros via chemical synthesis. Potential anti-bacterial activities against both erythromycin-susceptible and erythromycin-resistant bacteria were reported.
European journal of medicinal chemistry 10/2010; 45(12):5943-9. · 3.27 Impact Factor
-
Journal of Computer-Aided Molecular Design. 01/2010; 24:993-1008.
-
[show abstract]
[hide abstract]
ABSTRACT: The p38α mitogen-activated protein kinase (MAPK) has become an attractive target for the treatment of many diseases such as rheumatoid arthritis, inflammatory bowel disease and Crohn's disease. In this paper, 3D-QSAR and molecular docking studies were performed on 59 p38α MAPK inhibitors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to determine the structural requirements for potency in inhibiting p38α MAPK. The resulting model of CoMFA and CoMSIA exhibited good r(2) (cv) values of 0.725 and 0.609, and r(2) values of 0.961 and 0.905, respectively. Molecular docking was used to explore the binding mode between the inhibitors and p38α MAPK. We have accordingly designed a series of novel p38α MAPK inhibitors by utilizing the structure-activity relationship (SAR) results revealed in the present study, which were predicted with excellent potencies in the developed models. The results provided a useful guide to design new compounds for p38α MAPK inhibitors.
International Journal of Molecular Sciences 01/2010; 11(9):3357-74. · 2.60 Impact Factor
