Korean J Physiol Pharmacol.  2010 Dec;14(6):441-447. 10.4196/kjpp.2010.14.6.441.

Cytotoxic Activity and Structure Activity Relationship of Ceramide Analogues in Caki-2 and HL-60 Cells

• Kim YJ
• Kim EA
• Sohn UD
• Yim CB
• Im C

• KMID: 2071718
• DOI: http://doi.org/10.4196/kjpp.2010.14.6.441

Abstract

B13, a ceramide analogue, is a ceramidase inhibitor and induces apoptosis to give potent anticancer activity. A series of thiourea B13 analogues was evaluated for their in vitro cytotoxic activities against human renal cancer Caki-2 and leukemic cancer HL-60 in the MTT assay. Some compounds (12, 15, and 16) showed stronger cytotoxicity than B13 and C6-ceramide against both tumor cell lines, and compound (12) gave the most potent activity with IC50 values of 36 and 9 microM, respectively. Molecular modeling of thiourea B13 analogues was carried out by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). We obtained highly reliable and predictive CoMSIA models with cross-validated q2 values of 0.707 and 0.753 and CoMSIA contour maps to show the structural requirements for potent activity. These data suggest that the amide group of B13 could be replaced by thiourea, that the stereochemistry of 1,3-propandiol may not be essential for activity and that long alkyl chains increase cytotoxicity.

Keyword

B13; CoMFA; CoMSIA; Cytotoxicity; Ceramide

MeSH Terms

Apoptosis
Cell Line, Tumor
Ceramidases
Ceramides
HL-60 Cells
Humans
Inhibitory Concentration 50
Kidney Neoplasms
Models, Molecular
Structure-Activity Relationship
Thiourea
Ceramidases
Ceramides
Thiourea

Figure

• 

  Fig. 1. Structures of ceramide analogues.

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  Fig. 2. Plot of the actual versus predicted activities against tumor cell lines. (A) Renal cancer Caki-2 cells. (B) Leukemic cancer HL-60 cells. The IC50 values were converted into pIC50 (–log IC50) values (: training set molecules, ▴: test set molecules).

• 

  Fig. 3. 3D-contour maps of CoMSIA models. (A) CoMSIA model with steric and hydrogen bond donor fields for renal cancer Caki-2 cells. (B) CoMSIA model with steric and electrostatic fields for leukemic cancer HL-60 cells. Compound 12 is shown inside fields (green: sterically favorable; yellow: sterically unfavorable; cyan: hydrogen bond donor favorable; purple: hydrogen bond donor unfavorable; blue: positive charge favorable; red: negative charge favorable).

Reference

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