ABSTRACT
The synthesis of a new library of 4,4-disubstituted 3-methylidene-3,4-dihydro-2H-chroman-2-ones applying Horner-Wadsworth-Emmons methodology for the construction of an exo-methylidene moiety is reported. Corresponding 3-diethoxyphosphorylchroman-2-ones were synthesized in a three-step reaction sequence consisting of O-methylation of ethyl 2-diethoxyphosphoryl-3-oxoalkanoates, followed by reaction of the obtained 2-diethoxyphosphoryl-3-methoxy-2-alkenoates with phenols or 1-naphthol. The resulting 3-diethoxyphosphorylochromen-2-ones proved to be effective Michael acceptors in reactions with various Grignard reagents. Preliminary biological evaluations showed that many of the synthesized 3-methylidenechroman-2-ones possess very high cytotoxic activity against NALM-6 and HL-60 cancer cell lines (IC50 <1.0â µm) as well as high activity against the MCF-7 cancer cell line (IC50 <10â µm). Furthermore, two of the highly active 3-methylidenechroman-2-ones with geminal methyl and ethyl substituents at positionâ 4 showed promising therapeutic indexes of 10 and 13 in tests against human umbilical vein endothelial cells (HUVECs).
Subject(s)
Antineoplastic Agents/pharmacology , Coumarins/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Carboplatin/pharmacology , Coumarins/chemical synthesis , Coumarins/chemistry , HL-60 Cells , Human Umbilical Vein Endothelial Cells , Humans , Isomerism , MCF-7 Cells , Structure-Activity RelationshipABSTRACT
The main role of endogenous opioid peptides is the modulation of pain. Opioid peptides exert their analgesic activity by binding to the opioid receptors distributed widely in the central nervous system (CNS). However, opioid receptors are also found on tissues and organs outside the CNS, including the cells of the immune system, indicating that opioids are capable of exerting additional effects in periphery. Morphine, which is a gold standard in the treatment of chronic pain, is well-known for its immunosuppressive effects. Much less is known about the immunomodulatory effects exerted by endogenous (enkephalins, endorphins, dynorphins and endomorphins) and synthetic peptides activating opioid receptors. In this review we tried to summarize opioid peptide-mediated modulation of immune cell functions which can be stimulatory as well as inhibitory.
