Targeting Glycosylation Pathways and the Cell Cycle: Sugar-Dependent Activity of Butyrate-Carbohydrate Cancer Prodrugs

Abstract

Short-chain fatty acid (SCFA)-carbohydrate hybrid molecules that target both histone deacetylation and glycosylation pathways to achieve sugar-dependent activity against cancer cells are described in this article. Specifically, n-butyrate esters of N-acetyl-D-mannosamine (But4ManNAc, 1) induced apoptosis, whereas corresponding N-acetyl-D-glucosamine (But4GlcNAc, 2), D-mannose (But5Man, 3), or glycerol (tributryin, 4) derivatives only provided transient cell cycle arrest. Western blots, reporter gene assays, and cell cycle analysis established that n-butyrate, when delivered to cells via any carbohydrate scaffold, functioned as a histone deacetylase inhibitor (HDACi), upregulated p21WAF1/Cip1 expression, and inhibited proliferation. However, only 1, a compound that primed sialic acid biosynthesis and modulated the expression of a different set of genes compared to 3, ultimately killed the cells. These results demonstrate that the biological activity of butyrate can be tuned by sugars to improve its anticancer properties.

Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings

“…n-Butyrate, a naturally occurring short-chain fatty acid, is a well known histone deacetylase (HDAC) inhibitor [37]. In recent years, HDAC inhibition has attracted much attention for the development of anticancer drugs because HDAC inhibitors are able to disrupt cell cycle progression or selectively induce apoptosis via depression of certain genes [38][39][40][41]. Thus, the butyrate species liberated from the hydrolysis of these butyrylated derivatives may have contributed to the apparently higher potency of these compounds.…”

Chemical Biology of Cell Surface Oligosaccharides

“…In follow-up studies, our laboratory more thoroughly characterized the SCFA effects of butyrate appended to several monosaccharides, including ManNAc (Bu 4 ManNAc), mannose (Bu 5 Man), and GlcNAc (Bu 4 GlcNAc). We found that each of these hybrid compounds had the canonical activities expected from SCFAs, including histone deacetylase inhibition, up-regulation of p21 gene expression, and transient cycle-cell arrest that resulted in 3-to 5-day growth inhibition of cancer cell lines [73]. Only Bu 4 ManNAc, however, induced apoptosis in a variety of cancer lines.…”

“…10-5) have the potential to exacerbate perturbations to cellular physiology. To explain briefly, in the past, SCFAs such as acetates have been regarded as innocuous delivery agents; in reality, profound biological activities can be realized when using SCFA-sugar hybrids [12,[71][72][73]. For example, toxicity has long been associated with acetylation of sugars used in MOE, and although it is generally mild and not usually manifest in vivo, the underlying molecular mechanisms proved to be highly intriguing, as various N -acyl modifications of ManNAc were found to "tune" toxicity.…”

“…The connections between sialic acid production and SCFA biology revealed by Bu 4 ManNAc [72,73] are likely to be extremely difficult to understand in full molecular detail because both SCFA responses and glycosylation are highly complex on their own. When added together, additional intricacies are likely to emerge that link this SCFA metabolism and glycosylation; especially fascinating is long-established evidence of crosstalk between these two systems that has recently undergone renewed investigation.…”

Photochemical properties of a new kind of anti-cancer drug: N-glycoside compound

“…In the 1970s, chemists have synthesized Nglycoside compounds and proved that they had the anti-tumor activity. Japanese scholar Sampathkumar et al [1] have studied the anti-tumor activity of mannose with the hydroxyl group in C-2 being substituted by different amide groups. Nicolas Bridiau in France has confirmed that N-glycoside compounds have better stability with respect to glycosidase compared with O-glycoside compounds.…”