Synthesis and inhibitory activities against colon cancer cell growth and proteasome of alkylresorcinols.
We have identified alkylresorcinols (ARs) as the major active components in wheat bran against human colon cancer cell growth (HCT-116 and HT-29) using a bioassay-guided approach. To further study the structure-activity relationships, 15 ARs and their intermediates (1-15) were synthesized expediently by the modified Wittig reaction in aqueous media, and six 5-alkylpyrogallols and their analogues (16-21) were prepared by the general Grignard reaction. The synthetic AR analogues were evaluated for activities against the growth of human colon cancer cells HCT-116 and HT-29 and the chymotrypsin-like activity of the human 20S proteasome. Our results found that (1) AR C13:0 and C15:0 (13 and 14) had the greatest inhibitory effects in human colon cancer cells HCT-116 and HT-29, while decreasing or increasing the side chain lengths diminished the activities; (2) two free meta-hydroxyl groups at C-1 and C-3 on the aromatic ring of the AR analogues greatly contributed to their antitumor activity; (3) the introduction of a third hydroxyl group at C-2 (20 and 21) into the aromatic ring of the AR analogues yielded no significant enhancement in activity against HCT-116 cells and decimated the effects against HT-29 cells, but dramatically increased the activity against the chymotrypsin-like activity of the human 20S proteasome; and (4) AR C11:0 (12) was found to have the greatest effect in a series of AR C9:0-C17:0 against the chymotrypsin-like activity of the human 20S proteasome.
Center for Excellence in Post-Harvest Technologies, North Carolina Agricultural and Technical State University, North Carolina Research Campus, Kannapolis, North Carolina 28081, United States.
Yingdong
Y
Zhu
Dominique N
DN
Soroka
Shengmin
S
Sang
D000478:Alkylation; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000493:pharmacokinetics; D002455:Cell Division / Q000187:drug effects*; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D003110:Colonic Neoplasms / Q000473:pathology*; D004043:Dietary Fiber / Q000032:analysis*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011748:Pyrogallol / Q000737:chemistry; D012118:Resorcinols / Q000138:chemical synthesis* / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000972:Antineoplastic Agents, Phytogenic; D004043:Dietary Fiber; D012118:Resorcinols; D015842:Serine Proteinase Inhibitors; D011748:Pyrogallol; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex