Enantioselective Synthesis of Arglabin

Abstract

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Guaianolide Sesquiterpene Lactones, a Source To Discover Agents That Selectively Inhibit Acute Myelogenous Leukemia Stem and Progenitor Cells

“…Arglabin, an anticancer drug administrated by injection and which is currently in clinical trials in some countries, has a relatively narrow therapeutic index compared to DMAMCL. The LD 50 of arglabin by intraperitoneal injection is 190–220 mg in mice, and the MTD of arglabin by iv administration is around the same range as the effective dose (from 20 to 50 mg/kg daily for 20 days) . In summary, the significantly broader therapeutic index is the major advantage of DMAMCL over arglabin, and this result also suggests that administration routes may have an important effect on the therapeutic index.…”

“…The compounds contain α,β-unsaturated carbonyl structures, including SLs and their derivatives, as shown in Figures –. In comparison with PTL, several other commercially available SLs, including arglabin, dehydrocostus lactone ( 1 ), and costunolide ( 2 ), as well as artemsinin ( 3 ), which was reported to generate ROS to eradicate cancer cells, were evaluated for their anticancer activities. Since it is generally perceived that the α-methylene-γ-lactone moiety of SLs is responsible for their biological activities due to its interaction with biological nucleophiles, such as cysteine sulfhydryl groups of target proteins, by a Michael-type addition, − we also analyzed α-methylene-γ-lactone ( 4 ), itaconic anhydride ( 5 ), andrographolide ( 6 ), sarmentine ( 7 ), and a series of synthesized SL analogues ( 8 – 22 ) for their anticancer activities.…”

Catalytic Asymmetric Synthesis of Butenolides and Butyrolactones

“…Subsequent ozonolysis and reductive workup give rise to cyclopropanes 241 which can be readily converted into chiral disubstituted γ-butyrolactones 242 by diastereoselective nucleophile addition followed by a retroaldol/lactonization cascade (Scheme 134). This methodology has been applied to the asymmetric synthesis of several natural products including paraconic acids, 378 arglabin, 379 paeonilide, 380 atreludovicinolide, 381 and xanthatin. have been devoted to elucidating the reaction mechanisms as well as the origin of stereocontrol during the asymmetric transformation.…”

Discovery and resupply of pharmacologically active plant-derived natural products: A review

“…Yet, these synthetic endeavors are not reflected in the broad industrial manufacture of natural products. There is at least one total synthesis for each of the plant-derived natural products approved for therapeutic use in the last thirty years, presented in Table 1, with exemplary syntheses of (+)-artemisinin (Zhu and Cook, 2012), (+)-arglabin (Kalidindi et al, 2007), (−)-cannabidiol (Petrzilka et al, 1969), capsaicin (Kaga et al, 1989), (−)-colchicine (Lee et al, 1998), dronabinol ((−)-Δ 9 -trans-tetrahydrocannabinol (THC); (Trost and Dogra, 2007)), (+)-ingenol (as described in greater detail in the next paragraphs, ingenol is chemically converted to ingenol mebutate for therapeutic supply; (Liang et al, 2012)), masoprocol (meso-nordihydroguaiaretic acid; (Gezginci and Timmermann, 2001)), omacetaxine mepesuccinate ((−)-homoharringtonine; (Eckelbarger et al, 2008)), (−)-paclitaxel (Nicolaou et al, 1994), and (−)-solamargine (Wei et al, 2011a). Also found in this list is (−)-galanthamine, which is particularly notable because it is a rather complex plant-derived compound for which an entirely chemical industrial-scale production process exists (as described in detail in the next paragraphs).…”