Abstract
In a continuing search for curcuminoid (CUR) compounds with antitumor activity, a novel series of heterocyclic CUR–BF2 adducts and CUR compounds based on indole, benzothiophene, and benzofuran along with their aryl pyrazoles were synthesized. Computational docking studies were performed to compare binding efficiency to target proteins involved in specific cancers, namely HER2, proteasome, VEGFR, BRAF, and Bcl-2, versus known inhibitor drugs. The majority presented very good binding affinities, similar to, and even more favorable than those of known inhibitors. The indole-based CUR–BF2 and CUR compounds and their bis-thiocyanato derivatives exhibited high anti-proliferative and apoptotic activity by in vitro bioassays against a panel of 60 cancer cell lines, more specifically against multiple myeloma (MM) cell lines (KMS11, MM1.S, and RPMI-8226) with significantly lower IC50 values versus healthy PBMC cells; they also exhibited higher anti-proliferative activity in human colorectal cancer cells (HCT116, HT29, DLD-1, RKO, SW837, and Caco2) than the parent curcumin, while showing notably lower cytotoxicity in normal colon cells (CCD112CoN and CCD841CoN).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1895-1908 |
| Number of pages | 14 |
| Journal | ChemMedChem |
| Volume | 13 |
| Issue number | 18 |
| DOIs | |
| State | Published - Sep 19 2018 |
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Keywords
- antitumor agents
- apoptosis
- binding affinity
- curcuminoids
- multiple myeloma
ASJC Scopus subject areas
- Molecular Medicine
- Pharmacology, Toxicology and Pharmaceutics(all)
- Organic Chemistry
Cite this
Synthesis, Computational Docking Study, and Biological Evaluation of a Library of Heterocyclic Curcuminoids with Remarkable Antitumor Activity. / Laali, Kenneth K.; Greves, William J.; Zwarycz, Angela T.; Correa Smits, Sebastian J.; Troendle, Frederick J.; Borosky, Gabriela L.; Akhtar, Sharoon; Manna, Alak; Paulus, Aneel; Chanan Khan, Asher A; Nukaya, Manabu; Kennedy, Gregory D.
In: ChemMedChem, Vol. 13, No. 18, 19.09.2018, p. 1895-1908.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Synthesis, Computational Docking Study, and Biological Evaluation of a Library of Heterocyclic Curcuminoids with Remarkable Antitumor Activity
AU - Laali, Kenneth K.
AU - Greves, William J.
AU - Zwarycz, Angela T.
AU - Correa Smits, Sebastian J.
AU - Troendle, Frederick J.
AU - Borosky, Gabriela L.
AU - Akhtar, Sharoon
AU - Manna, Alak
AU - Paulus, Aneel
AU - Chanan Khan, Asher A
AU - Nukaya, Manabu
AU - Kennedy, Gregory D.
PY - 2018/9/19
Y1 - 2018/9/19
N2 - In a continuing search for curcuminoid (CUR) compounds with antitumor activity, a novel series of heterocyclic CUR–BF2 adducts and CUR compounds based on indole, benzothiophene, and benzofuran along with their aryl pyrazoles were synthesized. Computational docking studies were performed to compare binding efficiency to target proteins involved in specific cancers, namely HER2, proteasome, VEGFR, BRAF, and Bcl-2, versus known inhibitor drugs. The majority presented very good binding affinities, similar to, and even more favorable than those of known inhibitors. The indole-based CUR–BF2 and CUR compounds and their bis-thiocyanato derivatives exhibited high anti-proliferative and apoptotic activity by in vitro bioassays against a panel of 60 cancer cell lines, more specifically against multiple myeloma (MM) cell lines (KMS11, MM1.S, and RPMI-8226) with significantly lower IC50 values versus healthy PBMC cells; they also exhibited higher anti-proliferative activity in human colorectal cancer cells (HCT116, HT29, DLD-1, RKO, SW837, and Caco2) than the parent curcumin, while showing notably lower cytotoxicity in normal colon cells (CCD112CoN and CCD841CoN).
AB - In a continuing search for curcuminoid (CUR) compounds with antitumor activity, a novel series of heterocyclic CUR–BF2 adducts and CUR compounds based on indole, benzothiophene, and benzofuran along with their aryl pyrazoles were synthesized. Computational docking studies were performed to compare binding efficiency to target proteins involved in specific cancers, namely HER2, proteasome, VEGFR, BRAF, and Bcl-2, versus known inhibitor drugs. The majority presented very good binding affinities, similar to, and even more favorable than those of known inhibitors. The indole-based CUR–BF2 and CUR compounds and their bis-thiocyanato derivatives exhibited high anti-proliferative and apoptotic activity by in vitro bioassays against a panel of 60 cancer cell lines, more specifically against multiple myeloma (MM) cell lines (KMS11, MM1.S, and RPMI-8226) with significantly lower IC50 values versus healthy PBMC cells; they also exhibited higher anti-proliferative activity in human colorectal cancer cells (HCT116, HT29, DLD-1, RKO, SW837, and Caco2) than the parent curcumin, while showing notably lower cytotoxicity in normal colon cells (CCD112CoN and CCD841CoN).
KW - antitumor agents
KW - apoptosis
KW - binding affinity
KW - curcuminoids
KW - multiple myeloma
UR - http://www.scopus.com/inward/record.url?scp=85053051900&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053051900&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201800320
DO - 10.1002/cmdc.201800320
M3 - Article
C2 - 30079563
AN - SCOPUS:85053051900
VL - 13
SP - 1895
EP - 1908
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 18
ER -