Preparation of new alkyne-modified ansamitocins by mutasynthesis

Abstract

SummaryThe preparation of alkyne-modified ansamitocins by mutasynthetic supplementation of Actinosynnema pretiosum mutants with alkyne-substituted aminobenzoic acids is described. This modification paved the way to introduce a thiol linker by Huisgen-type cycloaddition which can principally be utilized to create tumor targeting conjugates. In bioactivity tests, only those new ansamitocin derivatives showed strong antiproliferative activity that bear an ester side chain at C-3.

The nuclear export inhibitor aminoratjadone is a potent effector in extracellular-targeted drug conjugates

“…Lysine residues were introduced in FA-N 3 -8 and FA-N 3 -9 to reduce charge, while increasing hydrophilicity. Additionally, we synthesized FA-SH-1 as a literature-known example for a sulfhydryl-containing folate carrier molecule 80,81. We next synthesized fluorescein-labeled folate conjugates (FA-FITC) by copper-mediated or metal-free azide–alkyne click chemistry with either the terminal-alkyne bearing 48 or the BCN-containing 49 (Fig.…”

Discovery of Small-Molecule Cyclic GMP-AMP Synthase Inhibitors

“…After the general procedure D, the corresponding arylbiguanide base, dimethyl oxalate (818 mg, 6.93 mmol), and 9.0 mL of MeOH were stirred at 35 °C for 3 h and then heated at reflux for 12 h. The reaction mixture was cooled to rt and concentrated to afford a gray-purple solid. The solid was purified by column chromatography (1−20% MeOH/CH 2 Cl 2 ) to afford a light purple solid (95 mg, 95% pure) in 11% yield: mp = 244−246 °C; 1 H NMR (DMSO-d 6 , 400 MHz) δ 10.3 (br s, 1H), 8.87 (s, 1H), 7.91 (dd, J = 8.6, 2.9 Hz, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.62 (br s, 1H), 3.84 (s, 3H); 13 (42). 6-Azido-N 2 -(4-iodophenyl)-1,3,5-triazine-2,4-diamine (72) (37 mg, 0.104 mmol), Et 3 NH (14.5 μL, 0.104 mmol), and copper iodide (5.9 mg, 0.031 mmol) were in anhydrous DMSO (0.416 mL) under N 2 .…”

“…Methyl 6-bromo-4-nitropicolinate (69). 42 6-Bromo-4nitropicolinic acid (1.21 mmol) was dissolved in anhydrous methanol followed by the addition of concentrated H 2 SO 4 (0.301 mmol). The mixture was heated at reflux overnight.…”

Anticancer activity and toxicity of new quaternary ammonium geldanamycin derivative salts and their mixtures with potentiators

“… 2 , 4 , 14–20 Moreover, modifications at the ansa -macrolide correlated to the preparation of conjugates with biotin, foliate, or within corporated triazole bridge, that gained molecular probe features of improved biocompatibility. 21–24 Overall, the ansa -bridge modifications of GDM led to a less effective anticancer potency than those performed at the rigid benzene or benzoquinone cores. 25–33 This can be attributed to a restriction of the ansa -bridge flexibility that is necessary for binding the GDM analogues to their molecular target, i.e.…”