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

Abstract

A series of carbamate derivatives of the antileukemic sesquiterpene melampomagnolide B (MMB) has been synthesized utilizing a 1,2,4-triazole carbamate conjugate of MMB as an intermediate synthon. Five imidazole- and benzimidazole-carbamate analogs of MMB (8a-8e) were prepared and evaluated for anti-leukemic activity against cultured M9 ENL1 AML cells. All the analogs exhibited improved anti-leukemic activity (EC50 = 0.90–3.93 μM) when compared to parthenolide and the parent sesquiterpene, MMB (EC50 = 7.0 μM and 15.5 μM, respectively). The imidazole carbamate analog, 8a (EC50 = 0.9 μM), was 16 times more potent than MMB. The comparative bioavailabilities of 8a and MMB and were determined in BALB/c mice following oral dosing of these compounds. It has been demonstrated that the absolute plasma bioavailabilities of MMB and 8a were 6.7 ± 0.8%, and 45.5 ± 2%, respectively. These results indicate that, compared to MMB, the PK parameters for 8a display significantly improved bioavailability and exposure after oral administration. Analog 8a is considered to be a potential clinical candidate for treatment of acute myelogenous leukemia.

Indole carboxylic acid esters of melampomagnolide B are potent anticancer agents against both hematological and solid tumor cells

“…Based on our previous work,[16–18] a series of novel heteroaromatic ester conjugates of MMB ( 7a–7o and 9 ) were prepared using standard EDC coupling conditions (Steglich type esterification) by reacting MMB ( 3 ) with an appropriate aryl carboxylic acid ( 6a–6o ) in the presence of EDCI and DMAP in dichloromethane at room temperature for 8 h. The heteroaryl carboxylic acids 6a–6o were chosen from a variety of available indole ( 6a–6l ), benzothiophene ( 6m–6n ), and benzofuran carboxylic acids, ( 6o ) to afford the corresponding MMB conjugates ( 7a–7o ) in yields ranging from 54% to 74% (Scheme 1 and Table 1). Indole carboxylic acids 6e and 6f were prepared from the commercially available methyl esters of these compounds by alkaline hydrolysis to the corresponding acids.…”

“…[13–15] The presence of the C-14 primary allylic hydroxyl group in the MMB molecule ( 3 , Figure 1) allows the medicinal chemist the opportunity to examine the biological activity of a wide variety of new MMB derivatives via conjugation and functional group transformations. Utilizing this approach, C-14 carbamate and carbonate conjugates of MMB have recently been shown to possess improved cytotoxicity against hematological and solid tumor cell lines when compared to the parent compound,[16–18] and the dimeric MMB carbamate esters ( 4 and 5, Figure 1) have been shown to possess promising anticancer activities against a wide variety of both hematological and solid human tumor cell lines. [17] The symmetrical MMB carbonate dimer ( 5 ) also exhibits superior anticancer activity against 9LSF gliosarcoma and M9-EML1 AML cells when compared to PTL and DMAPT.…”

MMB triazole analogs are potent NF-κB inhibitors and anti-cancer agents against both hematological and solid tumor cells

“…The sesquiterpene lactone MMB has been the source of several synthetic anti-leukemic molecules arising from our program over the past few years [3–6, 21]. In this respect, MMB can be conveniently synthesized from PTL utilizing a modification of the method of Macias et al [20] via a one-step selenium oxide oxidation of the C10 methyl group of PTL to a hydroxymethyl moiety.…”

“…Like PTL, MMB exhibits anti-leukemic properties [9]; however, unlike PTL, the structure of the MMB molecule provides more scope and greater opportunities for generating new chemical space around this interesting sesquiterpene lactone scaffold, since the molecule possesses an allylic hydroxyl group at C-14, which allows the synthesis of new MMB derivatives via conjugation and functional group transformations at this site. Thus, we have used a C-14 biotin-conjugated derivative of MMB for elucidating the mechanism of action of MMB in AML stem cells [9] and we have synthesized a variety of conjugated derivatives of MMB which exhibit potent anti-cancer activity against a wide variety of human cancer cell lines [3–6, 21]. We have also reported on some novel carbamate, and carbonate dimers of MMB (e.g.…”