Abstract
The present study involves the design of a series of 3-aryl-9-acetyl- pyridazino[3,4-b]indoles as constrained chalcone analogues. A retrosynthetic route was proposed for the synthesis of target compounds. All the synthesized compounds were evaluated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. The results indicated that 2a, 3a, 5a and 6a possessed significant cytotoxic potential with an IC50 value ranging from 1.13 to 5.76 μM. Structure activity relationship revealed that the nature of both Ring A and Ring B influences the activity. Substitution of methoxy groups on the phenyl ring (Ring A) and unsubstituted phenyl ring (Ring B) were found to be the preferred structural features. The most potent compound 2a was further tested for tubulin inhibition. Compound 2a was found to significantly inhibit the tubulin polymerization (IC50 value - 2.41 μM against THP-1). Compound 2a also caused disruption of microtubule assembly as evidenced by Immunoflourescence technique. The significant cytotoxicity and tubulin inhibition by 2a was rationalized by molecular modelling studies. The most potent structure was docked at colchicine binding site (PDB ID-1SA0) and was found to be stabilized in the cavity via various hydrophobic and hydrogen bonding interactions.
| Original language | English |
|---|---|
| Pages (from-to) | 648-660 |
| Number of pages | 13 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 85 |
| DOIs | |
| Publication status | Published - Oct 6 2014 |
| Externally published | Yes |
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Keywords
- Carboline
- Cell line
- Chalcone
- Constrained
- Cytotoxic
- Molecular modelling studies
- Tubulin
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
- Organic Chemistry
Cite this
Chalcone based azacarboline analogues as novel antitubulin agents : Design, synthesis, biological evaluation and molecular modelling studies. / Sharma, Sahil; Kaur, Charanjit; Budhiraja, Abhishek; Nepali, Kunal; Gupta, Manish K.; Saxena, A. K.; Bedi, P. M.S.
In: European Journal of Medicinal Chemistry, Vol. 85, 06.10.2014, p. 648-660.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chalcone based azacarboline analogues as novel antitubulin agents
T2 - Design, synthesis, biological evaluation and molecular modelling studies
AU - Sharma, Sahil
AU - Kaur, Charanjit
AU - Budhiraja, Abhishek
AU - Nepali, Kunal
AU - Gupta, Manish K.
AU - Saxena, A. K.
AU - Bedi, P. M.S.
PY - 2014/10/6
Y1 - 2014/10/6
N2 - The present study involves the design of a series of 3-aryl-9-acetyl- pyridazino[3,4-b]indoles as constrained chalcone analogues. A retrosynthetic route was proposed for the synthesis of target compounds. All the synthesized compounds were evaluated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. The results indicated that 2a, 3a, 5a and 6a possessed significant cytotoxic potential with an IC50 value ranging from 1.13 to 5.76 μM. Structure activity relationship revealed that the nature of both Ring A and Ring B influences the activity. Substitution of methoxy groups on the phenyl ring (Ring A) and unsubstituted phenyl ring (Ring B) were found to be the preferred structural features. The most potent compound 2a was further tested for tubulin inhibition. Compound 2a was found to significantly inhibit the tubulin polymerization (IC50 value - 2.41 μM against THP-1). Compound 2a also caused disruption of microtubule assembly as evidenced by Immunoflourescence technique. The significant cytotoxicity and tubulin inhibition by 2a was rationalized by molecular modelling studies. The most potent structure was docked at colchicine binding site (PDB ID-1SA0) and was found to be stabilized in the cavity via various hydrophobic and hydrogen bonding interactions.
AB - The present study involves the design of a series of 3-aryl-9-acetyl- pyridazino[3,4-b]indoles as constrained chalcone analogues. A retrosynthetic route was proposed for the synthesis of target compounds. All the synthesized compounds were evaluated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. The results indicated that 2a, 3a, 5a and 6a possessed significant cytotoxic potential with an IC50 value ranging from 1.13 to 5.76 μM. Structure activity relationship revealed that the nature of both Ring A and Ring B influences the activity. Substitution of methoxy groups on the phenyl ring (Ring A) and unsubstituted phenyl ring (Ring B) were found to be the preferred structural features. The most potent compound 2a was further tested for tubulin inhibition. Compound 2a was found to significantly inhibit the tubulin polymerization (IC50 value - 2.41 μM against THP-1). Compound 2a also caused disruption of microtubule assembly as evidenced by Immunoflourescence technique. The significant cytotoxicity and tubulin inhibition by 2a was rationalized by molecular modelling studies. The most potent structure was docked at colchicine binding site (PDB ID-1SA0) and was found to be stabilized in the cavity via various hydrophobic and hydrogen bonding interactions.
KW - Carboline
KW - Cell line
KW - Chalcone
KW - Constrained
KW - Cytotoxic
KW - Molecular modelling studies
KW - Tubulin
UR - http://www.scopus.com/inward/record.url?scp=84906081062&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84906081062&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2014.08.005
DO - 10.1016/j.ejmech.2014.08.005
M3 - Article
VL - 85
SP - 648
EP - 660
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -