Lipophilic analogs of sparsomycin as strong inhibitors of protein synthesis and tumor growth: a structure-activity relationship study

Abstract

Fourteen derivatives of sparsomycin (1) were synthesized. Six of them were prepared following a novel synthetic route starting from the L-amino acid alanine. Some physicochemical properties, viz. lipophilicity and water solubility, of selected derivatives were measured. The biological activity was tested in vitro in cell-free protein synthesis inhibition assays, in bacterial and tumor cell growth inhibition assays, and in the L1210 leukemia in vivo model in mice. Also for selected drugs the acute toxicity in mice was determined. Ribosomes from both an eukaryotic and a prokaryotic organism were used in the protein synthesis inhibition systems. A linear correlation between the lipophilicity parameters measured was observed. Water solubility and drug toxicity in mice were found to be linearly correlated with lipophilicity. All the derivatives studied are more lipophilic than 1. The deshydroxysparsomycin analogues (30-33) showed an interesting phenomenon: increase in hydrophobicity was accompanied by a considerable increase in water solubility. We found that an increase in hydrophobicity of the drug as a result of replacing the SMe group of 1 with larger alkylthio groups causes an increase in the biological activity of the drug. However, not only the hydrophobicity but also shape and size of the substituent are important; in the homologous series 1-9-10-11-12, 21-22-23-24, and 30-31-32-33, highest protein synthesis inhibitory and in vitro cytostatic activity is found with compounds 11, 23, and 32, respectively, and in comparison with the highly active n-butyl compound 10, the isomeric tert-butyl compound 13 is rather inactive. Polar substituents replacing the SMe group, i.e. Cl in 17 and 35, also render the molecule inactive. Substituting the bivalent sulfur atom for a methylene group decreases the drug's activity. This effect can be compensated for by increasing the length of the alkylsulfinyl side chain. The agreement between the results derived from cell-free and "in vivo" tests is good. The assays using ribosomes of bacterial and eukaryotic organisms give similar results although the latter seem to be more sensitive to changes in hydrophobicity of the drug. Our results confirm the presence of a hydrophobic region at the peptidyl transferase center of the ribosome; the interaction of sparsomycin with this region is more pronounced in the eukaryotic particles. The sparsomycin analogues 11, 23, and 30 show the highest antitumor activity against L1210 leukemia in mice, their median T/C values are 386, 330, and 216%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Toxicity Testing in the 21st Century: A Vision and a Strategy

“…Current applications of SAR analyses include soft drug design, which involves improving the therapeutic index of a drug by manipulating its steric and structural properties (Bodor, 1999); design and testing of chemotherapeutic agents (van den Broek et al, 1989); nonviral gene and targeted-gene delivery (Congiu et al, 2004); creating predictive models of carcinogenicity to replace animal models (Benigni, 2004); predicting the toxicity of chemicals, particularly pesticides and metals (Walker et al, 2003a); and predicting the environmental fate and ecologic effects of industrial chemicals (Walker et al, 2003b). Among the available predictive-toxicity systems, the most widely used are statistically based correlative programs (such as CASE/MultiCASE and TOPKAT) and rule-based expert systems (such as DEREK and ONCOLOGIC) (McKinney et al, 2000).…”

Ribosome‐mediated translational pause and protein domain organization

“…The preferred amino acids coded in slow regions are almost all decidedly hydrophobic, perhaps used to "stick" to the ribosome cavity also considered hydrophobic (van-den-Broek et al, 1989;Kim et al, 1991;Hardesty et al, 1992). It was reported earlier (Picking et al, 1991) that a synthesized hydrophobic polypeptide appeared to accumulate as a hydrophobic mass adjacent to the peptidyl transferase center on the ribosome, whereas polylysine extended directly from the ribosome into the surrounding solution.…”

Interaction of the antibiotic sparsomycin with the ribosome

“…The recent synthesis of a number of derivatives having up to 20-fold-higher inhibitory activity than the original drug (16,17) has rekindled interest in sparsomycin as an antitumor antibiotic, and some of these derivatives are currently at the level of clinical testing (19).…”