erbB-2 oncogene inhibition by geldanamycin derivatives: synthesis, mechanism of action, and structure-activity relationships

Abstract

Overexpression of the erbB-2 oncogene has been linked to poor prognosis in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the ansa ring of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2. Functional group modification in the ansa ring was performed stereoselectively and regiospecifically without the need for protection strategies. Essential functional groups that were required for anti-erbB-2 activity were the 7-carbamate and the 2,3-double bond. Modification of the functional groups at the other positions was permitted. Structure-activity relationships are described for 1-5-, 7-9-, 11-, 15-, and 22-substituted geldanamycins.

Structure-activity Relationships of Stemphones, Potentiators of Imipenem Activity against Methicillin-resistant Staphylococcus aureus

“…The resulting aqueous solution and the supernatant were mixed and extracted with EtOAc. The extracts were dried over Na 2 SO 4 and concentrated in vacuo to dryness to yield crude materials (6.4 g). The materials were dissolved in CHCl 3 , applied on a silica gel column (60 g), and eluted stepwise with 100 : 0 (100 ml), 100 : 1 (200 ml), 50 : 1 (300 ml), 10 : 1 (300 ml), 5 : 1 (300 ml) and 1 : 1 (300 ml) of CHCl 3 -CH 3 OH solvents (v/v).…”

“…Stemphone derivatives with a diversity at C-11 (C-11 derivatives) were prepared on the basis of the basic nucleophilic reaction [4]. To a solution of stemphone C (20 mg, 0.039 mmol) in pyridine (400 m l) 4-(dimethylamino) pyridine (5.0 mg, 0.040 mmol) and methanol (200 m l, 7.80 mmol) were added.…”

Heat shock protein inhibitors increase the efficacy of measles virotherapy

“…27,28 These agents disrupt HSP90 association with client proteins by occupying the nucleotide-binding site of HSP90, [29][30][31] therefore, preventing binding of HSP90 with ATP and affecting the composition of HSP90 containing multimolecular chaperone complexes. 32, 33 In view of evidence of activity in preclinical animal models, 34 …”

A New Post-PKS Modification Process in the Carbamoyltransferase Gene Inactivation Strain of Streptomyces hygroscopicus 17997

“…However, due to the occurrence of resistance and the hepatotoxicity of the current analogues, new GDM analogues with improved efficacy, reduced toxicity and favorable pharmacological profiles are in great demand [33,36]. Consequently, clear understand of GDM biosynthesis and the discovery of new post-tailoring enzymes should be useful for the development of new analogues.…”