Anti-cancer activity of carbamate derivatives of melampomagnolide B

Abstract

Melampomagnolide B (MMB) is a natural sesquiterpene structurally related to parthenolide (PTL). We have shown that MMB exhibits anti-leukemic properties similar to PTL. Unlike PTL, the presence of a primary hydroxyl group in the MMB molecule allows the opportunity for examining the biological activity of a variety of conjugated analogs of MMB. We have now synthesized a series of carbamate analogs of MMB and evaluated these derivatives for anti-cancer activity against a panel of sixty human cancer cell lines. Analogs 6a and 6e exhibited promising anti-leukemic activity against human leukemia cell line CCRF-CEM with GI50 values of 680 and 620 nM, respectively. 6a also showed GI50 values of 1.98 and 1.38 µM respectively, against RPMI-8226 and SR leukemia cell lines and GI50 values of 460 and 570 nM against MDA-MB-435 melanoma and MDA-MB-468 breast cancer cell lines, respectively. 6e had GI50 values of 650 nM and 900 nM against HOP-92 non-small cell lung and RXF 393 renal cancer cell lines.

Identification of a melampomagnolide B analog as a potential lead molecule for treatment of acute myelogenous leukemia

“…Initially, we investigated the synthesis of the C-14 imidazole and benzimidazole carbamate derivatives of MMB utilizing the p- nitrophenylchloroformate ester intermediate of MMB. 22 However, this conjugation procedure suffered from the drawback of low yields of the desired carbamate products and the production of unwanted C-13 Michael addition byproducts (5–10%). Also, although the p- nitrophenylchloroformate ester intermediate worked satisfactorily for strongly nucleophilic amines, it did not prove to be useful for poorly nucleophilic aromatic amines.…”

“…21 MMB is somewhat less potent than PTL, but both sesquiterpenes exhibit significantly reduced cytotoxicity against normal bone marrow stem cells when compared to their effect on AML stem cells. 21, 22 …”

“…Utilizing this approach, C-14 carbamate conjugates of MMB have recently been shown to possess improved cytotoxicity against hematological tumor cells and solid tumor cell lines when compared to the parent compound, 22,23 and a C-14 biotin-conjugated derivative of MMB has been prepared and used in elucidating the mechanism of action of MMB in primary human AML cells 11,16,21 .…”

Succinamide derivatives of melampomagnolide B and their anti-cancer activities

“…15 We have previously reported on the synthesis of a series of carbamate esters of MMB ( E , Fig. 1), that are potent cytotoxic agents against both hematological and solid tumor cancer cells lines, 16 and have also shown that dimeric carbamate and carbonate ester analogs of MMB ( F and G , Fig. 1) exhibit nanomolar cytotoxicity against a wide range of human cancer cells.…”

Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure–Activity Relationship Study

“…18,19 More recently, the Crooks lab generated a series of parthenolide and melampomagnolide-B analogues and screened them against a panel of 60 human cancer cell lines. 20–22 The α-methylene-γ- butyrolactone functionality was appended to small molecules to covalently link them to their biological target. 23,24 These compounds with α-methylene-γ-butyrolactone also show anticancer activities.…”