Macrocyclic ketone analogues of halichondrin B

Zheng, Wanjun; Seletsky, Boris M.; Palme, Monica H.; Lydon, Paul J.; Singer, Lori A.; Chase, Charles E.; Lemelin, Charles; Shen, Yongchun; Davis, Heather; Tremblay, Lynda; Towle, Murray J.; Salvato, Kathleen A.; Wels, Bruce F.; Aalfs, Kimberley K.; Kishi, Yoshito; Littlefield, Bruce A.; Yu, Melvin J.

doi:10.1016/j.bmcl.2004.08.069

Cited by 144 publications

(79 citation statements)

References 25 publications

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“…Further evidence that small structural changes can elicit large reversibility differences comes from previous studies of many HB analogs. In an analysis of more than 30 analogs of HB's macrocyclic pharmacophore, reversibility ratios of 1 to more than 100 were found (5,20). Indeed, after early observations that highly reversible analogs lacked in vivo activity, quantifying mitotic block reversibility became an integral part of medicinal chemistry optimization strategies that led to eribulin's discovery (5).…”

Section: Discussionmentioning

confidence: 99%

Eribulin Induces Irreversible Mitotic Blockade: Implications of Cell-Based Pharmacodynamics for In vivo Efficacy under Intermittent Dosing Conditions

Towle

Salvato²,

Wels³

et al. 2011

Cancer Research

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Eribulin (E7389), a mechanistically unique microtubule inhibitor in phase III clinical trials for cancer, exhibits superior efficacy in vivo relative to the more potent compound ER-076349, a fact not explained by different pharmacokinetic properties. A cell-based pharmacodynamic explanation was suggested by observations that mitotic blockade induced by eribulin, but not ER-076349, is irreversible as measured by a flow cytometric mitotic block reversibility assay employing full dose/response treatment. Cell viability 5 days after drug washout established relationships between mitotic block reversibility and long-term cell survival. Similar results occurred in U937, Jurkat, HL-60, and HeLa cells, ruling out cell type-specific effects. Studies with other tubulin agents suggest that mitotic block reversibility is a quantifiable, compound-specific characteristic of antimitotic agents in general. Bcl-2 phosphorylation patterns parallel eribulin and ER-076349 mitotic block reversibility patterns, suggesting persistent Bcl-2 phosphorylation contributes to long-term cell-viability loss after eribulin's irreversible blockade. Drug uptake and washout/retention studies show that [ Our results suggest that eribulin's in vivo superiority derives from its ability to induce irreversible mitotic blockade, which appears related to persistent drug retention and sustained Bcl-2 phosphorylation. More broadly, our results suggest that compound-specific reversibility characteristics of antimitotic agents contribute to interactions between cell-based pharmacodynamics and in vivo pharmacokinetics that define antitumor efficacy under intermittent dosing conditions. Cancer Res; 71(2); 496-505. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Eribulin Induces Irreversible Mitotic Blockade: Implications of Cell-Based Pharmacodynamics for In vivo Efficacy under Intermittent Dosing Conditions

Towle

Salvato²,

Wels³

et al. 2011

Cancer Research

Self Cite

136

107

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“…NSC 707839 (Littlefield et al, 2001;Zheng et al, 2004) was provided generously by the Eisai Research Institute (Andover, MA). Electrophoretically homogeneous bovine brain tubulin was prepared as described previously (Hamel and Lin, 1984), as was tubulin with [8-14 C]GDP bound in the exchangeable site (Duanmu et al, 1986), referred to, respectively, as appropriate, as tubulin-GDP and tubulin- [8-14 C]GDP.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Meanwhile, halichondrin B was synthesized de novo (Aicher et al, 1992), and this work led to syntheses of multiple "truncated" analogs (Littlefield et al, 2001;Zheng et al, 2004), including the macrocyclic ketone analog NSC 707389 (also known as E7389 and previously as ER-086526; Fig. 1).…”

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confidence: 99%

Comparison of the Activities of the Truncated Halichondrin B Analog NSC 707389 (E7389) with Those of the Parent Compound and a Proposed Binding Site on Tubulin

Burnett²,

et al. 2006

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The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on ␤-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. Neither compound seemed to induce an aberrant tubulin assembly reaction, as occurs with vinblastine (tight spirals) or dolastatin 10 (aggregated rings and spirals). We modeled the two compounds into a shared binding site on tubulin consistent with their biochemical properties. Of the two tubulin structures available, we selected for modeling the complex of a stathmin fragment with two tubulin heterodimers with two bound colchicinoid molecules and a single bound vinblastine between the two heterodimers (Nature (Lond) 435: 519 -522, 2005). Halichondrin B and NSC 707389 fit snugly between the two heterodimers adjacent to the exchangeable site nucleotide. Fitting the compounds into this site, which was also close to the vinblastine site, resulted in enough movement of amino acid residues at the vinblastine site to cause the latter compound to bind less well to tubulin. The model suggests that halichondrin B and NSC 707389 most likely form highly unstable, small aberrant tubulin polymers rather than the massive stable structures observed with vinca alkaloids and antimitotic peptides.From a structural viewpoint, halichondrin B (Fig. 1) is one of the most complex of the antitubulin compounds. Isolated from the sponges Halichondria okadai (Hirata and Uemura, 1986), Axinella species , and Lissodendoryx species (Litaudon et al., 1997), halichondrin B is a potent antimitotic agent that inhibits tubulin assembly (Bai et al., 1991). Because it inhibits the binding of radiolabeled vinblastine to tubulin in a noncompetitive manner, halichondrin B seems to bind in the "vinca domain" rather than in the same site on tubulin as the vinca alkaloids. Like most vinca domain drugs, halichondrin B inhibits both nucleotide exchange on ␤-tubulin (Bai et al., 1991) and formation of a cross-link between ␤-tubulin residues Cys12 and, probably, Cys211 (Ludueñ a et al., 1993). These properties have led to the assumption that the vinca domain was located near the exchangeable nucleotide site at the plus-end of the ␣␤-tubulin heterodimer, as defined in the electron crystallographic tubulin model (Nogales et al., 1998), in which Cys12 is only a few angstroms from the guanine residue of the exchangeable GDP. The recent success in locating the vinca site using crystals of two ␣␤-tubulin-colchicinoid complexes bound to a

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“…These agents are extracted from sponges or marine organisms or synthesized chemically, and exert growth-inhibitory activities in vitro and in vivo against various types of human cancer cells (7,8). Halichondrin B is an MCK of high molecular weight (approximately 1060 Da).…”

Section: Discussionmentioning

confidence: 99%

“…However, there have been few reports to date regarding the activities of MCKs similar to the lactone compounds (7,8). These compounds have the highest molecular weights (approximately 1,060 Da) of the MCKs.…”

Section: Introductionmentioning

confidence: 99%

Antitumor and anti-invasive effects of diverse musk-fragrant macrocyclic ketones and their enhancement by hyperthermia

Kageyama

2011

Mol Med Report

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Abstract. The antitumor and anti-invasive activities of the low-molecular-weight macrocyclic ketones (MCKs), such as musk secreted from the mammalian genital glands and musk released from relatively unkown plants, were investigated comparatively together with the enhancement of the effects in combination with hyperthermia. Ehrlich ascites tumor cells were treated with each MCK and cultured, followed by evaluation of the cell viability using the mitochondrial dehydrogenase-based WST-8 assay. The number of HT-1080 human fibrosarcoma cells cultured with the MCKs or invading through a reconstituted basement membrane was measured using microscopy. The order of the efficiency was as follows: (Z)-g-cycloheptadecen-1-one (Hp) (17:1, musk rats), 8-cyclohexadecen-1-one (16:1, musk ferns), cyclopentadecanone (15:0, musk rats) and 3-methylcyclopentadecanone (16:0, musk deer), having 15-17 carbon atoms with and without a double bond, which exhibited a carcinostatic effect either at 100 µM for 20-h culture or at 50 µM for 72-h culture. The effects were markedly enhanced by heat treatment at 42˚C. MCKs were not found in the cells by gas-liquid chromatographic determination, indicating that the carcinostatic effects were attributed to their surface activity on the cell membrane. Invasion of HT-1080 cells was inhibited by MCKs at doses scarcely diminishing the cell viability, indicating that the suppression of invasiveness did not ensue from the secondary action due to carcinostasis. The order of invasion-inhibitory efficacy of the MCKs was, however, similar to that of their carcinostatic effects. Hp17:1 also exhibited the highest anti-invasive activity in addition to the highest carcinostatic activity. The two inhibitory effects were promoted by combination with hyperthermia. MCKs with a double bond, particularly Hp17:1 rather than 8-Hx16:1, but not saturated-aliphatic MCKs, may be potent multi-applicable antitumor agents due to their dual inhibitory activities against tumor progression and invasion and in hyperthermia-combined therapy. IntroductionThe anti-cancer activity of natural macrocyclic lactones (1,2) and delta-lactones isolated from plants or fungi (3,4) have been reported. We extensively studied the activity of their synthesized compounds and previously reported the activity of the low-molecular-weight delta-alkyllactones and macrocyclic lactones (5,6).However, there have been few reports to date regarding the activities of MCKs similar to the lactone compounds (7,8). These compounds have the highest molecular weights (approximately 1,060 Da) of the MCKs. With regard to the low-molecular-weight (224-250 Da) MCKs contained in musks secreted from the mammalian genital gland, these MCKs are quite chemically different from conventional substances. Their anti-tumor activity has yet to be elucidated.In the present study, the carcinostatic activity of the MCKs was studied using Ehrlich ascites tumor (EAT) cells. The carcinostatic effects were evaluated by a decrease in mitochondrial dehydrogenase activity reflecting the sur...

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Macrocyclic ketone analogues of halichondrin B

Cited by 144 publications

References 25 publications

Eribulin Induces Irreversible Mitotic Blockade: Implications of Cell-Based Pharmacodynamics for In vivo Efficacy under Intermittent Dosing Conditions

Eribulin Induces Irreversible Mitotic Blockade: Implications of Cell-Based Pharmacodynamics for In vivo Efficacy under Intermittent Dosing Conditions

Comparison of the Activities of the Truncated Halichondrin B Analog NSC 707389 (E7389) with Those of the Parent Compound and a Proposed Binding Site on Tubulin

Antitumor and anti-invasive effects of diverse musk-fragrant macrocyclic ketones and their enhancement by hyperthermia

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