Synthesis and biological activity of spergualin analogues. I.

Abstract

Stable spergualin analogues were synthesized by substitutions of the or-hydroxyglycine residue of spergualin with various a-or <y-amino acids.The antitumor activity of these analogues against LI210 and their immunosuppressive effects on delayed-type hypersensitivity and antibody formation was then examined. Analogues substituted with glycine and L-serine showed significant biological activity but were less potent than 1 5-deoxyspergualin.Among the analogues synthesized so far, 104A^-(4-guanidinophenyl)butyryl-L-seryl]-1 ,5,10-triazadecane has possessed the strongest antitumor and immunosuppressive activities.Spergualin, (-)-(156r)-l -amino-19-guanidinol l, 15-dihydroxy-4, 9, 12-triazanonadecane-10, 13-dione, is an antiturnor antibiotic isolated from culture filtrates of Bacillus laterosporus BMG-162-aF2.1 ' 2) Recently, the immunosuppressive activity of spergualin has been reported.3) The total synthesis of spergualin has been accomplished.43 The structure and antitumor activity relationships of spergualin analogues and derivatives against L1210 were also studied. Deoxyspergualin, the 15-deoxy analogue of spergualin, showed stronger antitumor5) and immunosuppressive6) activities than spergualin. This demonstrated that the 15-hydroxyl group was not essential for manifestation of these activities. These analogues, however, were unstable due to an unusual hemiaminal structure at 10~12 position in the molecule. Consequently they hydrolyzed gradually into an o>-guanidino-fatty acid amide and a hydrate of glyoxyloylspermidine in an aqueous solution as shown in Scheme 1.In this paper, the syntheses and structure activity of stable spergualin analogues are reported in which the a-hydroxyglycine residue corresponding to 10~12 position of deoxyspergualin is substituted with various a-or w-aminoacids. Scheme1. Degradation of spergualins in an aqueous solution.

Heat Shock Protein 70 (Hsp70) as an Emerging Drug Target

“…Thus, this approach allows ready variation of the amino acid identity. However, in antitumor assays against L1210 leukemia cells, only the glycine ( 3 ) and L-serine ( 4 ) derivatives retained activity, whereas even conservative replacements with alanine or leucine abolished function 137. Likewise, variations in the polyamine regions, such as the number of methyl groups or secondary amines, decreased efficacy 135.…”

Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

“…Subsequent work showed that this molecule has anticancer and immunosuppressive activities [112][113][114]. Synthetic efforts have removed some of the metabolic liabilities of spergualin, including the hydroxyl at carbon 15, which have greatly improved the physical properties of the chemical series [115,116]. The most advanced of the spergualin analogs, 15-deoxyspergualin (15-DSG), is clinically approved in Japan for the treatment of acute allograft rejection, making this molecule the lone Hsp70 inhibitor approved for human use [117,118].…”

“…Early SAR studies were focused on three key regions of 15-DSG, the central α-hydroxyglycine core, the guanidylated fatty chain, and the spermidine-derived polyamine. Nishizawa and coworkers replaced the central α-hydroxyglycine with various α-or ω-amino acids, and the antitumor activities of these analogs were evaluated against L1210 (IMC) mouse leukemia cells [115]. From the resulting SAR, the authors concluded that the central α-hydroxyglycine could be replaced with either glycine or an L-serine residue.…”

Targeted Imaging Agent to HSP70 Induced In Vivo

“…Several groups synthesized this compound but they reported low yields (7%-12%). [36][37][38][39][40][41][42][43][44][45][46] In this report, we describe an improved DSG synthesis according to the published methods with some major modification of reaction conditions with high yields (overall 18%-22%). Recently, several groups developed and evaluated the HSPtargeted imaging agents.…”