Synthesis and Structure−Activity Relationship of Griseofulvin Analogues as Inhibitors of Centrosomal Clustering in Cancer Cells

Rønnest, Mads H.; Rebacz, Blanka; Markworth, Lene; Terp, Anette Hinsch; Larsen, Thomas Ostenfeld; Krämer, Alwin; Clausen, Mads Hartvig

doi:10.1021/jm801517j

Cited by 64 publications

(81 citation statements)

References 25 publications

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“…22,27 Alkylation of 4 to synthesize 5 and 6 has previously been described. 22,27 Position 4 analogues 7 and 8 were prepared from 4 with Ag 2 O and the appropriate alkyl bromide in dioxane as solvent. 27 The syntheses of 9 and 10 have already been described.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…35 The analogues with an oxime functionality 36, 37, and 38 were synthesized from the corresponding ketones (1, 17, and 26) using hydroxylamine hydrochloride in ethanol and DMSO. 13,22 Isogriseofulvin (39−44) and griseofulvin analogues (45−49 and 17) were synthesized simultaneously in pairs by solvolysis Analogues 50−55 were synthesized according to published procedures ( Figure 2). 22 The fungal secondary metabolite geodin (56) was recently isolated from Aspergillus terreus.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Looking at the IC 50 values for the 16 analogues (1, 17, 18, 20, 23−25, 27, 36, 37, 45−49, and 54) tested active in both the multipolarity assay 19 and the cytotoxicitybased assay there was good correlation between the data with an R 2 of 0.70 (see Supporting Information). The IC 50 of griseofulvin (1) was determined to be 18 ± 4 μM (20 ± 1 μM in the phenotype-based spindle multipolarity assay 22 ), while an IC 50 of 25 ± 4 μM against HeLa cells was found by Panda et al 18 In the position 4 series, 4, 5, and 7 were all inactive but 6 and 8 harboring aromatic moieties had activities similar to griseofulvin (1), with IC 50 values of 20 (6) and 17 μM (8). This indicates a mode of action for cytotoxicity that does not involve induction of multipolar mitosis, as 6 was inactive in the multipolarity assay.…”

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confidence: 99%

“…2′-Chloro analogue 16 has previously been observed by us to have a different phenotype from all other analogues in the cell-based assay for multipolarity induction. 22 The highly electrophilic nature of 16 prompted an investigation of the ability of this analogue, together with 1 and 17, to act as Michael acceptors. Briefly, the three compounds were incubated in buffer with two different potential nucleophiles, 2-aminoethanol and 2-mercaptoethanol, for up to seven days (see Supporting Information for details).…”

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confidence: 99%

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Disparate SAR Data of Griseofulvin Analogues for the Dermatophytes Trichophyton mentagrophytes, T. rubrum, and MDA-MB-231 Cancer Cells

et al. 2012

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Griseofulvin and 53 analogues of this compound have been tested against the pathogenic dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes as well as against the breast cancer cell line MDA-MB-231. The modifications to griseofulvin include the 4, 5, 6, 2′, 3′, and 4′ positions. The SAR of the griseofulvin analogues toward the two fungi followed the same trend with the majority being less active than griseofulvin and none had more than twice the potency of the parent compound. A comparison of the antifungal and the anticancer SAR revealed distinct differences, as the majority of analogues showed increased activity against the cancer cell line MDA-MB-231, highlighted by 2′-benzyloxy-2′-demethoxy-griseofulvin, which showed low activity against both fungi but was among the most potent compounds against MDA-MB-231 cancer cells. Tubulin has been proposed as the target of griseofulvin in both fungal and mammalian cells, but the differences revealed by this SAR study strongly suggest that the mode-of-action of the compound class toward fungi and mammalian cancer cells is different.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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confidence: 99%

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Disparate SAR Data of Griseofulvin Analogues for the Dermatophytes Trichophyton mentagrophytes, T. rubrum, and MDA-MB-231 Cancer Cells

et al. 2012

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“…Using a phenotype-based screening strategy, we have recently found that griseofulvin induces spindle multipolarity, mitotic arrest, and subsequent cell death in multiple tumor cell lines but not in diploid fibroblasts and keratinocytes with normal centrosome content (13). Chemical optimization of griseofulvin led to the development of compounds with significantly increased activity and mean inhibitory concentrations (IC 50 ) of proliferation and survival in the lower micromolar range when applied to the human squamous cell carcinoma cell line SCC114, which had been used for the initial screening (21).…”

Section: Introductionmentioning

confidence: 99%

GF-15, a Novel Inhibitor of Centrosomal Clustering, Suppresses Tumor Cell Growth In Vitro and In Vivo

et al. 2012

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In contrast to normal cells, malignant cells are frequently aneuploid and contain multiple centrosomes. To allow for bipolar mitotic division, supernumerary centrosomes are clustered into two functional spindle poles in many cancer cells. Recently, we have shown that griseofulvin forces tumor cells with supernumerary centrosomes to undergo multipolar mitoses resulting in apoptotic cell death. Here, we describe the characterization of the novel small molecule GF-15, a derivative of griseofulvin, as a potent inhibitor of centrosomal clustering in malignant cells. At concentrations where GF-15 had no significant impact on tubulin polymerization, spindle tension was markedly reduced in mitotic cells upon exposure to GF-15. Moreover, isogenic cells with conditional centrosome amplification were more sensitive to GF-15 than parental controls. In a wide array of tumor cell lines, mean inhibitory concentrations (IC 50 ) for proliferation and survival were in the range of 1 to 5 mmol/L and were associated with apoptotic cell death. Importantly, treatment of mouse xenograft models of human colon cancer and multiple myeloma resulted in tumor growth inhibition and significantly prolonged survival. These results show the in vitro and in vivo antitumor efficacy of a prototype small molecule inhibitor of centrosomal clustering and strongly support the further evaluation of this new class of molecules. Cancer Res; 72(20); 5374-85. Ó2012 AACR.

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Direct Oxidative Disulfenylation/Cyclization of 2′‐Hydroxyacetophenones with Thiophenols for the Synthesis of 2,2‐Dithio‐Benzofuran‐3(2H)‐Ones

Zhang

Zhao

et al. 2018

Adv Synth Catal

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A direct oxidative disulfenylation/cyclization of 2'-hydroxyacetophenones with thiophenols mediated by TBAI/K 2 S 2 O 8 has been successfully developed within this study. The reaction successfully provides an efficient method for the synthesis of functionalized 2,2-dithio-benzofuran-3(2H)-ones, which exhibits readily available starting materials, a broad substrate scope, excellent yields, and large-scale applicability. In a single step, two CÀS bonds and one CÀO bond are simultaneously built on the same sp 3 carbon atom under transitionmetal-free conditions.

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Synthesis and Structure−Activity Relationship of Griseofulvin Analogues as Inhibitors of Centrosomal Clustering in Cancer Cells

Cited by 64 publications

References 25 publications

Disparate SAR Data of Griseofulvin Analogues for the Dermatophytes Trichophyton mentagrophytes, T. rubrum, and MDA-MB-231 Cancer Cells

Disparate SAR Data of Griseofulvin Analogues for the Dermatophytes Trichophyton mentagrophytes, T. rubrum, and MDA-MB-231 Cancer Cells

GF-15, a Novel Inhibitor of Centrosomal Clustering, Suppresses Tumor Cell Growth In Vitro and In Vivo

Direct Oxidative Disulfenylation/Cyclization of 2′‐Hydroxyacetophenones with Thiophenols for the Synthesis of 2,2‐Dithio‐Benzofuran‐3(2H)‐Ones

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