Optimization, pharmacophore modeling and 3D-QSAR studies of sipholanes as breast cancer migration and proliferation inhibitors.
Sipholenol A, a triterpene isolated from the Red Sea sponge Callyspongia siphonella, was previously shown to reverse multidrug resistance in P-glycoprotein-overexpressing cancer cells. Moreover, sipholanes showed promising in vitro inhibitory effects against the invasion and migration of the metastatic human breast cancer cell line MDA-MB-231. The breast tumor kinase (Brk), a mediator of cancer cell phenotypes important for proliferation, survival, and migration, was proposed as a potential target. This study reports additional semisynthetic optimization of sipholenol A esters to improve the breast cancer antimigratory and antiproliferative activities as well as Brk phosphorylation inhibition. Fifteen new sipholenol A analogs (25-39) were semisynthesized. Sipholenol A 4β-4',5'-dichlorobenzoate ester (29) was the most potent, with an IC50 value of 1.3 μM in the migration assay. The level of Brk phosphorylation inhibition of 29 was assessed using the Z'-LYTE™ kinase assay and Western blot analysis. Active analogs showed no toxicity on the non-tumorigenic epithelial breast cell line MCF10A at doses equal to their IC50 values or higher in migration and proliferation assays, suggesting their selectivity towards malignant cells. Pharmacophore modeling and 3D-QSAR studies were conducted to identify important pharmacophoric features and correlate 3D-chemical structure with activity. These studies provided the evidence for future design of novel antimigratory compounds based on a simplified sipholane structure possessing rings A and B (perhydrobenzoxepine) connected to substituted aromatic esters, with the elimination of rings C and D ([5,3,0]bicyclodecane system). This will enable the future synthesis of the new active entities feasibly and cost-effectively. These results demonstrate the potential of marine natural products for the discovery of novel scaffolds for the control and management of metastatic breast cancer.
Department of Basic Pharmaceutical Sciences of College of Pharmacy, University of Louisiana at Monroe, USA.
Ahmed I
AI
Foudah
Department of Basic Pharmaceutical Sciences of College of Pharmacy, University of Louisiana at Monroe, USA.
Asmaa A
AA
Sallam
Department of Basic Pharmaceutical Sciences of College of Pharmacy, University of Louisiana at Monroe, USA.
Mohamed R
MR
Akl
Department of Basic Pharmaceutical Sciences of College of Pharmacy, University of Louisiana at Monroe, USA. Electronic address: elsayed@ulm.edu.
Khalid A
KA
El Sayed
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D021281:Quantitative Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D014315:Triterpenes; C523549:sipholenol A; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human
3D-QSAR; Antimigratory; Antiproliferative; Breast cancer; Brk; Pharmacophore modeling; Sipholane