115122-59-3Relevant academic research and scientific papers
Anhydride modified cantharidin analogues: Synthesis, inhibition of protein phosphatases 1 and 2A and anticancer activity
McCluskey, Adam,Bowyer, Michael C.,Collins, Elizabeth,Sim, Alistair T.R.,Sakoff, Jennette A.,Baldwin, Monique L.
, p. 1687 - 1690 (2000)
Two series of anhydride modified cantharidin analogues were synthesised and screened for their phosphatase inhibition (PP1 and PP2A) and cytotoxicity in various cancer cell lines (Ovarian A2780, ADDP; Osteosarcoma 143B; and Colon HCT116 and HT29). One series was synthesised by a novel, high yielding one-pot hydrogenation-ring-opening-esterification procedure, the other by acid catalysed acetal formation. Analogues 5-7 and 9 displayed moderate PP2A selectivity (ca. 5- to 20-fold) and inhibition typically in the low μM range (comparable, in some cases to cantharidin). The anticancer activity of these analogues varied with the cell line under study; however, many of them showed selective cytotoxicity for the colon tumour cell lines. (C) 2000 Elsevier Science Ltd. All rights reserved.
Cantharidin analogues: Synthesis and evaluation of growth inhibition in a panel of selected tumour cell lines
McCluskey, Adam,Ackland, Stephen P.,Bowyer, Michael C.,Baldwin, Monique L.,Garner, James,Walkom, Cecilia C.,Sakoff, Jennette A.
, p. 68 - 79 (2003)
Diels-Alder addition of furans (furan, furfuryl alcohol, and 3-bromofuran) to maelic anhydride yields three distinct 5,6-dehydronorcantharidins. Hydrogenation of (4,10-dioxatricyclo[5.2.1.0]decane-3,5-dione) (4a), in dry ethanol affords the monoester (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic aid monoethyl ester) (6). Subsequent transesterification affords a series of monoesters (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monomethyl ester (7)), 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monopropyl ester (8), (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monohexyl ester (9)) and differentially substituted diesters (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-ethyl ester 3-isopropyl ester) (10), and (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-ethyl ester 3-phenyl ester) (11). Analogues were firstly screened for their ability to inhibit protein phosphatases 1 (PP1) and 2A (PP2A) as the lead compounds cantharidin (1) and norcantharidin (2) are known PP1 and PP2A inhibitors. Only analogues 4a, 6-8 displayed good PP1 and PP2A inhibition (PP1 IC50's=2.0, 2.96, 4.71, and 4.82μM, respectively; PP2A IC50's=0.2, 0.45, 0.41, and 0.47μM, respectively). All analogues were also screened for their anti-cancer potential against a panel of tumour cell lines, HL60, L1210, SW480, WiDr, HT29, HCT116, A2780, ADDP, and 143B, producing GI50 values ranging from 6μM to >1000μM. Analogues possessing good PP1 and/or PP2A inhibition also returned moderate to good anti-cancer activity. Analogues with substituents directly attached to the intact bicyclo[2.2.1]heptane skeleton were poor to moderate anti-cancer agents. This correlates well with their lack of PP1 or PP2A activity. Analogues capable of undergoing a facile ring opening of the anhydride or with a single carboxylate were good PP1 and PP2A inhibitors, largely correlating to the observed anti-cancer activity in all cases, except 11. Analogue 11, whist neither a PP1 nor a PP2A inhibitor shows anti-cancer activity comparable to 1 and 2. We believe that intracellular esterases generate the corresponding dicarboxylate, which is a potent PP1 and PP2A inhibitor, and that it is this species which is responsible for the observed anti-cancer activity.
Natural drug composition modified derivative and anti-tumor application thereof
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, (2019/04/17)
The invention discloses a camptothecin derivative I and a synthesis method thereof in the field of new drug design and synthesis. The structural formula of the camptothecin derivative I is as shown inthe specification, R in the formula I is selected from H, Br or dehydrogenation, and R1 is selected from C1-C3 alkyl, naphthenic base, benzyl and substituted benzyl. Activity tests prove that the designed and synthesized camptothecin derivative I has excellent anti-tumor effects and particularly is high in liver cancer, stomach cancer, colon cancer and pancreatic cancer activity.
A flow chemistry approach to norcantharidin analogues
Tarleton, Mark,Young, Kelly A.,Unicomb, Elli,McCluskey, Siobhann N.,Robertson, Mark J.,Gordon, Christopher P.,McCluskey, Adam
experimental part, p. 568 - 574 (2012/06/05)
Acid-ester and acid-amide norcantharidin derivatives are prepared using a 'one-pot' synthetic procedure utilizing the ThalesNano H-cube flow hydrogenator. Traditionally, rapid library generation and reaction scale up of these analogues was limited by the batch wise hydrogenation of 5,6-dehydronorcantharidin. This was resolved with the use of flow chemistry. With no associated scale up issues, a method was devised to produce norcantharidin, along with acid-ester and acid-amide analogues on any scale necessary for biological screening.
