Bioactive Flavaglines: Synthesis and Pharmacology

Update on Phytochemical and Biological Studies on Rocaglate Derivatives from Aglaia Species

“…Several review articles have appeared recently by various groups on the pharmacological activities of rocaglates and have dealt, in particular, with their antineoplastic [14,25,111], antiviral [111,112], and miscellaneous biological effects [14]. In terms of drug development, work on a synthetic derivative of rocaglamide (1), eFT-226 (27,Zotatifin), which was elucidated to have good pharmacokinetic properties and potent antitumor effects, like rocaglamide (1) and DDR (3), seems promising. The potent eIF4A inhibitor, Zotatifin, is the first compound with this mechanism of action to have entered into a clinical trial as a potential treatment for patients with advanced solid-tumor malignancies [113].…”

“…In addition to episilvestrol (5‴-episilvestrol) (9), a small number of additional structural modified variants of silvestrol ( 8) have ▶ Fig. 2 Structures of cytotoxic rocaglates isolated from various Aglaia species and several related synthetic congeners (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

“…1 ). The presence of a dioxanyl ring was demonstrated to enhance the cytotoxic potency of rocaglates 2 , 22 , 23 and has led to extensive work on the synthesis and structure-activity requirement exploration of rocaglamide, silvestrol, and related analogs 22 , 23 , 24 , 25 , 26 , 27 , 28 .…”

“…Structures of cytotoxic rocaglates isolated from various Aglaia species and several related synthetic congeners(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

Structurally Modified Cyclopenta[b]benzofuran Analogues Isolated from Aglaia perviridis

“…Over the last four decades, several species of the genus Aglaia , belonging to the plant family Meliaceae, have been investigated for their phytochemical composition, resulting in the isolation of cyclopenta­[ b ]­benzofuran compounds (flavaglines) such as rocaglamide, didesmethylrocaglamide, silvestrol ( 6 ), − and various thapkapsins and thapoxepines. , These phytochemicals are of considerable interest due to their potential biological activities such as antibacterial, antitumor, antiviral, insecticidal, and neuroprotective effects. − In particular, rocaglamide, silvestrol ( 6 ), and its structural analogue 5‴-episilvestrol (episilvestrol, 7 ) have been found to act as potent apoptotic and cytostatic agents, ,, leading to a growing interest in their biological activity and total synthesis. Several groups have worked successfully on the complete enantioselective synthesis of silvestrol and episilvestrol, which contain a dioxanyl ring in their structures, − enabling a better understanding of the structure–activity relationship of flavaglines and their possible development as therapeutic leads, such as against B-cell malignancies. , Mechanistic investigations of the flavaglines have demonstrated them to arrest the G2/M phase of the cell cycle, , with rocaglamide acting as a prohibitin (PHB) 1 and 2 inhibitor , and silvestrol ( 6 ) and episilvestrol ( 7 ) determined as eIF4A protein translation inhibitors. ,, A recent study further evaluated the structural mechanism of rocaglamide as a translation initiation inhibitor where the ATP-independent high structural selectivity of these compounds for the molecular interface formed between the eIF4A1 protein and the polypurine bases on mRNA was shown .…”