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Chemoselective fluorination and chemoinformatic analysis of griseofulvin: Natural vs fluorinated fungal metabolites.

Abstract：

:Griseofulvin is a fungal metabolite and antifungal drug used for the treatment of dermatophytosis in both humans and animals. Recently, griseofulvin and its analogues have attracted renewed attention due to reports of their potential anticancer effects. In this study griseofulvin (1) and related analogues (2-6, with 4 being new to literature) were isolated from Xylaria cubensis. Six fluorinated analogues (7-12) were synthesized, each in a single step using the isolated natural products and Selectflour, so as to examine the effects of fluorine incorporation on the bioactivities of this structural class. The isolated and synthesized compounds were screened for activity against a panel of cancer cell lines (MDA-MB-435, MDA-MB-231, OVCAR3, and Huh7.5.1) and for antifungal activity against Microsporum gypseum. A comparison of the chemical space occupied by the natural and fluorinated analogues was carried out by using principal component analysis, documenting that the isolated and fluorinated analogues occupy complementary regions of chemical space. However, the most active compounds, including two fluorinated derivatives, were centered around the chemical space that was occupied by the parent compound, griseofulvin, suggesting that modifications must preserve certain attributes of griseofulvin to conserve its activity.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Paguigan ND,Al-Huniti MH,Raja HA,Czarnecki A,Burdette JE,González-Medina M,Medina-Franco JL,Polyak SJ,Pearce CJ,Croatt MP,Oberlies NH

doi

10.1016/j.bmc.2017.07.041

subject

Has Abstract

pub_date

2017-10-15 00:00:00

pages

5238-5246

issue

20

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(17)31232-4

journal_volume

25

pub_type

杂志文章

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