Restraining the flexibility of the central linker in terameprocol results in constrained analogs with improved growth inhibitory activity.
The semi-synthetic lignan terameprocol inhibits the transcription of several inflammatory and oncogenic genes and has been evaluated for its anti-cancer properties. Here we investigated the effect of restricting the flexibility of the carbon linker connecting the terminal rings of terameprocol on its growth inhibitory activity. Conformational restriction was explored by introducing unsaturation, inserting polar entities with limited flexibility and cyclization of the connecting linker. Twenty three compounds were synthesized and evaluated on a panel of malignant human cells. The most promising compounds were those with non-polar linkers, as seen in butadiene 1a and the cyclized benzylideneindane analog 7. Both compounds were more potent than terameprocol on pancreatic BxPC-3 cells with GI50 values of 3.4 and 8.1 μM, respectively. Selected isomers of 1a (E,E) and 7 (Z) adopted low energy bent conformations that mimicked the low energy conformer of terameprocol. It is tempting to propose that conformational similarity to terameprocol may have contributed to their good activity. The scaffolds of 1a and 7 should be further investigated for their anticancer potential.
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Republic of Singapore.
Sherman Si Han
SS
Ho
Mei Lin
ML
Go
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D009637:Masoprocol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects
D000970:Antineoplastic Agents; C076852:terameprocol; D009637:Masoprocol
Constrained analogs; Growth inhibitory activity; Structure–activity relationship; Terameprocol