Synthesis and antiproliferative properties of a new ceramide analog of varacin

Abstract

A benzopentasulfane was synthesized in 8 steps with a ceramide attached through an amide bond to the 7-position of the heterocycle structure. The anticancer activity of this synthetic ceramide-benzopolysulfane drug conjugate was analyzed against five human cancer cell lines MDA-MB-231 (breast), DU145 (prostate), MIA PaCa-2 (pancreas), HeLa (cervix), and U251 (glioblastoma). The ceramide-benzopolysulfane conjugate had IC50 values ranging from 10 to >20 μM with complete cell killing at 12.5 μM for MDA-MB-231and 20 μM for DU145 and HeLa cells. The ceramide-benzopolysulfane conjugate had IC50 values 1.8 and 4.0 times lower than a PEG benzopolysulfane, N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzo[f][1,2,3,4,5]-pentathiepine-7-carboxamide, for MDA-MB-231 and DU145 cells, respectively. The parent “unsubstituted” benzopolysulfane, o-C6H4S5, had IC50 values 4.2 times lower and 2.7 times higher than the ceramide benzopolysulfane for MDA-MB-231and DU145 cells, respectively. The results indicate that the polysulfur linkage is needed for activity since benzenedithiol, o-C6H4(SH)2, had IC50 values greater than 30 μM with little effect on MDA-MB-231 and DU145 cells. Thus, to account for the bioactivity, a bimolecular reaction of cellular thiol with the ceramide benzopolysulfane is a proposed followed by thiozone (S3) extrusion.

Investigation of the Pentathiepin Functionality as an Inhibitor of Feline Immunodeficiency Virus (FIV) via a Potential Zinc Ejection Mechanism, as a Model for HIV Infection

“…The substituted indoles 25 a and 25 b provided good activities, with the ethyl substitution being preferred over the methyl, but further examples would be needed to probe the potential of this result. This could also include creation of a conjugate, as recently exemplified by Greer and co‐workers to increase cell penetration …”

“…The substituted indoles 25 a and 25 b provided good activities, with the ethyl substitution being preferred over the methyl, but furthere xamples would be needed to probe the potentialo ft his result.T his could also include creationo faconjugate, as recentlye xemplified by Greer and co-workerstoi ncrease cell penetration. [72] During the course of our investigations we also demonstrated the validity of the FIV model for use as aH IV-1 surrogate with 53 %s equence similarity in the minimizedm odel ChemMedChem 2019, 14,454 -461 www.chemmedchem.org (Figure 9), which is supported by an umber of recentr eviews. [73][74][75] The sub-micromolar potencies of these compounds coupled with moderate toxicities show an interesting avenue of investigation toward the development of ac andidate compound for targetingt he FIV/HIV NCp.…”

SG1002 and Catenated Divalent Organic Sulfur Compounds as Promising Hydrogen Sulfide Prodrugs

“…In 2010, Greer et al ( 166 ) described the synthesis and in vitro anticancer properties of a number of highly cytotoxic hydrophilic PEGylated benzopentathiepins, and in 2016 the Greer lab reported ( 165 ) on the synthesis, characterization, and in vitro anticancer properties of a lipophilic ceramide analog. On both occasions, antiproliferative effects were studied only on human malignant cell lines; therefore, at this time it is extremely difficult to estimate the probability of successful clinical development of an anticancer drug based on a pentathiepin pharmacophore.…”

Sphingolipids: promising lipid-class molecules with potential applications for industry. A review

“…For example, sphingosine (4-sphingenine) can be coupled with phenethyl isothiocyanate to possess increased inhibitory activity towards human leukemia cell growth, when compared to sphingosine itself (Xu et al, 2000). A coupling of sphingosine with benzopentasulfane led to formation of ceramidebenzopolysulfane conjugate that possesses enhanced inhibitory activity against human breast cancer cells, in comparison to parent unsubstituted benzopolysulfane (Mahendran et al, 2015). Sphingosine can be also modified to alkynyl-sphingomyelin (Sandbhor et al, 2009), in a series of reactions that includes: sphingosine conversion into 2-azido-sphingosine, phosphorylation of 2-azido-sphingosine, with its amination by means of alkynylammonium head-group and final N-acylation with fatty acid to obtain alkyne-modified sphingomyelin.…”