Design, Synthesis, and Cytotoxicity Evaluation of Novel Griseofulvin Analogues with Improved Water Solubility.

Ahmed K Hamdy,Atef A Abdel-Hafez,Samia A Shouman,Mahmoud M Sheha

doi:10.1155/2017/7386125

Ahmed K Hamdy, Atef A Abdel-Hafez + Show 2 more

Open Access

https://doi.org/10.1155/2017/7386125

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Abstract

Griseofulvin 1 is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Study of SAR of some griseofulvin analogues has led to the identification of 2′-benzyloxy griseofulvin 3, a more potent analogue which retards tumor growth through inhibition of centrosomal clustering. However, similar to griseofulvin 1, compound 3 exhibited poor aqueous solubility. In order to improve the poor water solubility, six new griseofulvin analogues 5–10 were synthesized and tested for their antiproliferative activity and water solubility. The semicarbazone 9 and aminoguanidine 10 analogues were the most potent against HCT116 and MCF-7 cell lines. In combination studies, compound 9 was found to exert synergistic effects with tamoxifen and 5-fluorouracil against MCF-7 and HCT116 cells proliferation, respectively. The flow cytometric analysis of effect of 9 on cell cycle progression revealed G2/M arrest in HCT116. In addition, compound 9 induced apoptosis in MCF-7 cells. Finally, all synthesized analogues revealed higher water solubility than griseofulvin 1 and benzyloxy analogue 3 in pH 1.2 and 6.8 buffer solutions.

Highlights

Griseofulvin 1, a natural product from Penicillium griseofulvum, was first discovered in 1939 and has been known for its antifungal properties in guinea pigs and man since 1958 [1,2,3,4]
The mode of action of griseofulvin 1 has been the subject of large research efforts, where it was reported that 1 binds to tubulin [10], inhibits tubulin polymerization, and disturbs microtubule dynamics [11, 12]
The carboxymethoxime analogue 5 was synthesized through alkylation of 4 with chloroacetic acid

Summary

Introduction

Griseofulvin 1, a natural product from Penicillium griseofulvum, was first discovered in 1939 and has been known for its antifungal properties in guinea pigs and man since 1958 [1,2,3,4]. The selectivity of 1 against tumor cells is due to its ability to inhibit centrosomal clustering in vitro [13]. Inhibition of centrosomal clustering may constitute a novel therapeutic target for selective eradication of cancer cells with multiple centrosomes [13,14,15]. The benzyloxy analogue 3 was found to be the most potent against MDA-MB-231 and SCC 114 cell lines [16, 17] with a 25-fold increase in activity as a centrosome clustering inhibitor compared to 1. It was reported that the benzyloxy analogue 3 retards tumor growth in murine xenograft models of colon cancer and multiple myeloma through in vivo inhibition of centrosomal clustering [17, 18]. In addition to biological activity, griseofulvin 1 and analogues hereof were subjected to solubility study at simulated gastric (pH 1.2) and intestinal (pH 6.8) buffer solutions

Results and Discussion

Biological Investigations

Conclusion

Experimental Section