CURCUMIN ANALOGUES AS ANTICANCER DRUG CANDIDATE: DESIGN, SYNTHESIS AND CYTOTOXICITY TEST
Curcumin is natural product that contains turmeric (Curcuma longa L). The biological activity of curcumin has been tested such as antioxidants, antibacterial, antifungal, anti-viral, anti-inflammatory and anti-angiogenic as well as agents for degenerative diseases such as anti-Alzheimer's, a...
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Curcumin is natural product that contains turmeric (Curcuma longa L). The
biological activity of curcumin has been tested such as antioxidants, antibacterial,
antifungal, anti-viral, anti-inflammatory and anti-angiogenic as well as agents for
degenerative diseases such as anti-Alzheimer's, anti-cancer and others. The
obstacle faced in development of curcumin is the substance has poor absorption,
low solubility, rapid metabolism and elimination and poor bioavailability. Several
strategies to increase the bioavailability of curcumin i.e. co-using with adjuvant, in
nanoparticles form, metal-curcumin complexes, development of new compounds of
curcumin analogous, as well as conjugation and bioconjugation.
The present study developed new curcumin analogues which was designed with
ligand-based pharmacophore similarity approach. The searching of lead
compounds was the first step in design of new analogues. The structure of lead
compounds was the basis for determining pharmacophores model, and it was then
the basis for designing new compounds of curcumin analogues.
The curcumin analogue designed results were then studied their physicochemical
and pharmacokinetic properties by druglikeness analysis approach, with curcumin
as a reference compound. The interaction between curcumin analogues and
DYRK2 protein was also studied. DYRK2 is a cancer receptor that is widely studied
in searching anticancer candidates because of its role as proteasome regulator.
Cells with DYRK2 deficiency show a slower proliferation. The designed curcumin
analogues were synthesized for in vitro cytotoxicity study against HeLa cell
(cervical cancer cell), WiDR (colon cancer cell), HepG2 (liver cancer cell), T47D
(breast cancer cell), MCF-7 (breast cancer cell) and Vero (normal cell) with using
curcumin and cisplatin as reference molecules.
The pharmacophore analysis of lead compounds (curcumin and 23 curcumin
analogues which are proven as inhibitors of ?B cell proliferation) have selected a
pharmacophore model with the features of H-bond donor and acceptor from
hydroxyl groups (-OH) which are bound to para-positions of aromatic ring,
aromatic feature, and H-bond acceptor from carbonyl oxygen.
The compound design using the feature similarity of pharmacophore model has
resulted in six curcumin analogue, i.e. (1E, 4E) -1,5-bis (4-hydroxyphenyl) penta
1,4-dien-3-one, or dihydroxidibenzalaseton (DOHDAC); (1E, 4E) -1,5-bis (3,4-
dihydroxyphenyl) penta-1,4-dien-3-one, or tetrahydroxy-dibenzalacetone
(TOHDAC); ((1E, 4E) -3-oxopenta-1,4-diene-1,5-diyl) bis (4,1-phenylene)
diacetate, or diacetatedibenzalacetone (DADBAC) ((1E, 4E) -3-oxopenta-1 , 4-
diene-1,5-diyl) bis (benzene-4,1,2-triyl) tetraacetate, or
tetraacetatedibenzalacetone (TADBAC); diethyl 2,2 '- (((((1E, 4E) -3-oxopenta1,4-diene-1,5-diyl) bis (4,1-phenylene)) bis (oxy)) diacetate, or diethylacetate- Odibenzalacetone (DEAODBAC); and 4-formyl-1,2-phenylene diacetate, or
diacetatebenzaldehyde (DABA).
Based on the prediction of membrane absorption and permeability using logP and
logD values, it was shown that the six curcumin analogues were able to penetrate
into biological membranes well. The results of prediction of drug distribution in
crossing the blood-brain barrier showed that the six curcumin analogues had better
penetration ability than that of curcumin. Six curcumin analogues did not inhibit
CYP3A4, while DEAODBAC and DOHDBAC could become CYP3A4 substrates.
Six curcumin analogues showed a predictive half-life above 0.5 which means they
can be recommended as good drug candidates. Based on the FDAMDD prediction
results, it shows that curcumin and six curcumin analogues are not toxic.
The molecular docking simulation showed that the affinity of TOHDBAC (-13.62
kcal/mol) and DOHDBAC (-12.48 kcal mol) was better than that of curcumin (-
12.46 kcal/mol) in their interaction with DYRK2 protein (PDB code: 5ZTN).
Molecular dynamics simulations showed that the six curcumin analogues had more
negative binding energy with DYRK2 than that of curcumin (-53,058 kJ/mol), thus
it was predicted to have higher anticancer activity than curcumin. Curcumin is the
nature ligand of DYRK2.
The results of cytotoxicity evaluation showed that the TOHDBAC has best
cyitotoxic activity as shown by IC50 values: against HeLa cells (2.95 µM), WiDR
(5.33 µM), T47D (4.26 µM) and HepG2 (18.56 µM). Its cytotoxicity is better than
curcumin. The IC50 of TOHDBAC value was also better than that of cisplatin
against HeLa, WiDR, and HepG2 cells. DOHDBAC (2.34 µM) and DADBAC (5.39
µM) had better IC50 than that of curcumin and cisplatin against HepG2. The
cytotoxicity test on Vero cells showed that cisplatin and curcumin had higher
cytotoxicity than that of six curcumin analogues.
|
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author |
Ode Aman, La |
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Ode Aman, La CURCUMIN ANALOGUES AS ANTICANCER DRUG CANDIDATE: DESIGN, SYNTHESIS AND CYTOTOXICITY TEST |
author_facet |
Ode Aman, La |
author_sort |
Ode Aman, La |
title |
CURCUMIN ANALOGUES AS ANTICANCER DRUG CANDIDATE: DESIGN, SYNTHESIS AND CYTOTOXICITY TEST |
title_short |
CURCUMIN ANALOGUES AS ANTICANCER DRUG CANDIDATE: DESIGN, SYNTHESIS AND CYTOTOXICITY TEST |
title_full |
CURCUMIN ANALOGUES AS ANTICANCER DRUG CANDIDATE: DESIGN, SYNTHESIS AND CYTOTOXICITY TEST |
title_fullStr |
CURCUMIN ANALOGUES AS ANTICANCER DRUG CANDIDATE: DESIGN, SYNTHESIS AND CYTOTOXICITY TEST |
title_full_unstemmed |
CURCUMIN ANALOGUES AS ANTICANCER DRUG CANDIDATE: DESIGN, SYNTHESIS AND CYTOTOXICITY TEST |
title_sort |
curcumin analogues as anticancer drug candidate: design, synthesis and cytotoxicity test |
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id-itb.:544702021-03-17T10:22:05ZCURCUMIN ANALOGUES AS ANTICANCER DRUG CANDIDATE: DESIGN, SYNTHESIS AND CYTOTOXICITY TEST Ode Aman, La Indonesia Dissertations curcumin analogue, ADMET and interaction prediction, synthesis, in vitro cytotoxicity test INSTITUT TEKNOLOGI BANDUNG https://digilib.itb.ac.id/gdl/view/54470 Curcumin is natural product that contains turmeric (Curcuma longa L). The biological activity of curcumin has been tested such as antioxidants, antibacterial, antifungal, anti-viral, anti-inflammatory and anti-angiogenic as well as agents for degenerative diseases such as anti-Alzheimer's, anti-cancer and others. The obstacle faced in development of curcumin is the substance has poor absorption, low solubility, rapid metabolism and elimination and poor bioavailability. Several strategies to increase the bioavailability of curcumin i.e. co-using with adjuvant, in nanoparticles form, metal-curcumin complexes, development of new compounds of curcumin analogous, as well as conjugation and bioconjugation. The present study developed new curcumin analogues which was designed with ligand-based pharmacophore similarity approach. The searching of lead compounds was the first step in design of new analogues. The structure of lead compounds was the basis for determining pharmacophores model, and it was then the basis for designing new compounds of curcumin analogues. The curcumin analogue designed results were then studied their physicochemical and pharmacokinetic properties by druglikeness analysis approach, with curcumin as a reference compound. The interaction between curcumin analogues and DYRK2 protein was also studied. DYRK2 is a cancer receptor that is widely studied in searching anticancer candidates because of its role as proteasome regulator. Cells with DYRK2 deficiency show a slower proliferation. The designed curcumin analogues were synthesized for in vitro cytotoxicity study against HeLa cell (cervical cancer cell), WiDR (colon cancer cell), HepG2 (liver cancer cell), T47D (breast cancer cell), MCF-7 (breast cancer cell) and Vero (normal cell) with using curcumin and cisplatin as reference molecules. The pharmacophore analysis of lead compounds (curcumin and 23 curcumin analogues which are proven as inhibitors of ?B cell proliferation) have selected a pharmacophore model with the features of H-bond donor and acceptor from hydroxyl groups (-OH) which are bound to para-positions of aromatic ring, aromatic feature, and H-bond acceptor from carbonyl oxygen. The compound design using the feature similarity of pharmacophore model has resulted in six curcumin analogue, i.e. (1E, 4E) -1,5-bis (4-hydroxyphenyl) penta 1,4-dien-3-one, or dihydroxidibenzalaseton (DOHDAC); (1E, 4E) -1,5-bis (3,4- dihydroxyphenyl) penta-1,4-dien-3-one, or tetrahydroxy-dibenzalacetone (TOHDAC); ((1E, 4E) -3-oxopenta-1,4-diene-1,5-diyl) bis (4,1-phenylene) diacetate, or diacetatedibenzalacetone (DADBAC) ((1E, 4E) -3-oxopenta-1 , 4- diene-1,5-diyl) bis (benzene-4,1,2-triyl) tetraacetate, or tetraacetatedibenzalacetone (TADBAC); diethyl 2,2 '- (((((1E, 4E) -3-oxopenta1,4-diene-1,5-diyl) bis (4,1-phenylene)) bis (oxy)) diacetate, or diethylacetate- Odibenzalacetone (DEAODBAC); and 4-formyl-1,2-phenylene diacetate, or diacetatebenzaldehyde (DABA). Based on the prediction of membrane absorption and permeability using logP and logD values, it was shown that the six curcumin analogues were able to penetrate into biological membranes well. The results of prediction of drug distribution in crossing the blood-brain barrier showed that the six curcumin analogues had better penetration ability than that of curcumin. Six curcumin analogues did not inhibit CYP3A4, while DEAODBAC and DOHDBAC could become CYP3A4 substrates. Six curcumin analogues showed a predictive half-life above 0.5 which means they can be recommended as good drug candidates. Based on the FDAMDD prediction results, it shows that curcumin and six curcumin analogues are not toxic. The molecular docking simulation showed that the affinity of TOHDBAC (-13.62 kcal/mol) and DOHDBAC (-12.48 kcal mol) was better than that of curcumin (- 12.46 kcal/mol) in their interaction with DYRK2 protein (PDB code: 5ZTN). Molecular dynamics simulations showed that the six curcumin analogues had more negative binding energy with DYRK2 than that of curcumin (-53,058 kJ/mol), thus it was predicted to have higher anticancer activity than curcumin. Curcumin is the nature ligand of DYRK2. The results of cytotoxicity evaluation showed that the TOHDBAC has best cyitotoxic activity as shown by IC50 values: against HeLa cells (2.95 µM), WiDR (5.33 µM), T47D (4.26 µM) and HepG2 (18.56 µM). Its cytotoxicity is better than curcumin. The IC50 of TOHDBAC value was also better than that of cisplatin against HeLa, WiDR, and HepG2 cells. DOHDBAC (2.34 µM) and DADBAC (5.39 µM) had better IC50 than that of curcumin and cisplatin against HepG2. The cytotoxicity test on Vero cells showed that cisplatin and curcumin had higher cytotoxicity than that of six curcumin analogues. text |