The synthetic and biological studies of discorhabdins and related compounds

Abstract

Various analogues of the marine alkaloids, discorhabdins, have been synthesized. The strategy contains spirocyclization with phenyliodine(III) bis(trifluoroacetate) (PIFA), oxidative fragmentation of the β-amino alcohols with the hypervalent iodine reagent C(6)F(5)I(OCOCF(3))(2), the detosylation and dehydrogenation reaction of the pyrroloiminoquinone unit in the presence of a catalytic amount of NaN(3) and the bridged ether synthesis with HBr-AcOH as the key reactions. All the synthesized compounds were evaluated by in vitro MTT assay for cytotoxic activity against the human colon cancer cell line HCT-116. Furthermore, the discorhabdin A oxa analogues were also evaluated against four kinds of tumor model cells, a human colon cancer cell line (WiDr), a human prostate cancer cell line (DU-145) and murine leukemia cell lines (P388 and L1210). For the identification of the target, discorhabdin A and the discorhabdin A oxa analogue were evaluated by an HCC panel assay. In the test, discorhabdins could have a novel mode of action with the tumor cells.

Exploration of the Electrophilic Reactivity of the Cytotoxic Marine Alkaloid Discorhabdin C and Subsequent Discovery of a New Dimeric C-1/N-13-Linked Discorhabdin Natural Product

“…Collectively these studies characterise the electrophilic reactivity of the spiro-dienone moiety of discorhabdin C, a structural feature that is known to be a factor, but not the sole determinant, for the cytotoxicity reported for this class of alkaloid [ 15 , 16 , 17 ]. To further explore the degree of essentiality of the dienone ring towards cytotoxicity, discorhabdin C was subjected to hydrogenation using Pd/C under an H 2 atmosphere for 15 min to afford, after workup, a blue-coloured product in 71% yield.…”

“…Together these results prompted us to evaluate the antiparasitic activities of a series of discorhabdin natural products and semi-synthetic analogues that we have previously shown to exhibit modest or minimal tumour cell line cytotoxicity. Included in this study were (+)-discorhabdin B 1 , discorhabdin C 2 , 6 – 8 , 3-dihydrodiscorhabdin C 9 [ 15 ], (+)-discorhabdin D 10 , (-)-discorhabdin H 11 , (+)-discorhabdin H 2 12 [ 19 ] (-)-discorhabdin L 13 , discorhabdin Q 14 , discorhabdin U 15 , semi-synthetic dienone-phenol 16 [ 23 ] and discorhabdin B dimer 17 [ 5 , 16 ] ( Figure 8 ).…”

“…In many cases, discorhabdin alkaloids have been reported to exhibit cytotoxicity towards tumour cell lines [ 1 , 2 , 3 , 4 , 6 , 8 , 9 ], with additional biological activities also including inhibition of protein–protein interaction associated with hypoxia-inducible factor 1α and its transcriptional coactivator p300 [ 10 , 11 ], antibacterial [ 12 , 13 , 14 ] and antimalarial [ 13 ] properties. The biological activities of simple dienone-containing examples of the discorhabdins has been attributed to the electrophilic properties of this moiety [ 2 , 15 ]. We have studied this mode of reactivity for discorhabdin B ( 1 ), finding that reactions with thiols including N -acetyl- l -cysteine affords C-1 thiol substituted C-2/N-18 ring closed analogues (e.g., 3 , Figure 2 ) [ 16 ] and that semi-synthetic derivatives that lack electrophilic reactivity exhibit less potent cytotoxicity.…”

Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma

“…The NSC 668394 binding affinity (K D = 10.6± 2.9μM) in comparison to analogue 21a , which showed no binding to ezrin, suggested that the 3,5 dibromo-4-hydroxy substitution pattern on the aryl ring is important for ezrin binding. Addition of hydroxyl substituents on the aromatic group as shown for analogues 21f 21 and 21g resulted in slightly increased binding affinity to ezrin. Substitution of the bromine atoms with chlorine atoms as shown in analogue 21k also resulted in a statistically significant increase in ezrin-binding potency.…”

SAR of Sponge-Inspired Hemibastadin Congeners Inhibiting Blue Mussel PhenolOxidase

“…Tetraiodo-norbromohemibastadin-1 ( 4 ) was synthesized by iodination of 2 , utilizing a modified method of Wada et al [ 11 ]. Briefly, 2 (157.0 mg, 0.5 mmol) was dissolved in diluted sodium hydroxide solution (5 mL, pH 10), and H 2 O 2 (30% aqueous solution, 0.12 mL) and iodine (I 2 , 152.0 mg, 0.6 mmol) were added.…”