Three group of novel sulfonylurea podophyllotoxin derivatives were designed synthesized and evaluated for cytotoxicity against four tumor cell lines (A-549 DU-145 KB and KBvin). improve cytotoxic activity. family. It exerts cytotoxic activity by inhibiting microtubule assembly.1 2 Enormous progress has been achieved concerning the structural elements required for activity. These findings led to authorization of etoposide (3) and teniposide (4) two semisynthetic glucoside derivatives of 4′-O-demethylepipodophyllotoxin (2) as well as etopophos (5) a water-soluble prodrug of 3 as anticancer medicines. Unlike 1 compounds 3-5 exert cytotoxic activity by inhibiting DNA topoisomerase II.3-7 Improved understanding of the mechanism(s) of action along with considerable structure-activity and pharmacology studies reenergized desire for further modification studies within the C-4 substituent of 2 to increase antitumor activity. Accordingly numerous C-4 substituents were launched into the parent molecule leading to either enhanced or similar activity. Through C4 changes some non-sugar substituted analogues especially a similar method to that defined above for 11 and 12. Finally using very similar solutions to those for 13a-l and 14a-e focus on compounds 21a-c had AT13148 been extracted from 20 in produces which range from 67% to 82%. All recently synthesized compounds had been purified by column chromatography and their buildings were verified by 1H-NMR 13 and ESI-MS data. 2.2 Cytotoxicity and SAR Focus on substances 13a-l 14 and 21a-c had been evaluated for in vitro cytotoxicity against four individual tumor cell lines A549 (non-small cell lung cancers) DU145 (prostate cancers) KB (nasopharyngeal carcinoma) and KBvin [multi-drug resistant (MDR) KB subline selected using vincristine] utilizing a sulforhodamine B colorimetric (SRB) assay with triplicate tests.24 Substance 3 was included as positive control and the full total email address details are CT5.1 summarized in Desk 1. Desk 1 In vitro cytotoxicity of 13a-l 14 and 21a-c against four individual tumor cell lines with etoposide (3) as control. Notably substances 14c and 14e demonstrated excellent activity (IC50 1.41-1.76 and 1.72-2.01 μM respectively) weighed against 3 (IC50 2.03-3.88 μM) against A549 DU-145 and KB tumor cell lines. Most of all these two substances maintained significant cytotoxicity (IC50 1.76 and 2.01 μM respectively) against the medication resistant KBvin tumor cell AT13148 series while 3 dropped its activity completely (IC50 > 20 μM). This result is within agreement with this prior observation that C4-amino substitution of 2 is normally favorable for conquering drug-resistance.25 Although offered and 4′-Linnaeus as the beginning material for preparation of most new derivatives. The beginning sulfonylcarbamates were ready based on the method reported previously.27 28 The main element intermediate 4β-amino congeners 11 12 and AT13148 20 had been synthesized by our previously reported techniques and their buildings confirmed by direct evaluation with a geniune test and previously reported spectroscopic data.21 22 4.2 General man made procedure for focus on substances 13a-l 14 and 21a-c Essential intermediates 11 12 and 20 (0.2 mmol) were added dropwise to a remedy of 0.4 mmol of sulfonylcarbamate in dried out toluene (20 mL). The response mix was refluxed for 2~4 h and focused. The residue was purified by chromatography on silica gel using CHCl3/MeOH as eluant to AT13148 give 13a-l 14 and 21a-c which were stable both at chemical purification stage and under assay conditions. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 521.0 [M+H]+. AT13148 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 535.0 [M+H]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 585.1 [M+Na]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 583.3 [M+H]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 630.5 [M+NH4]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 597.0 [M+H]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 624.3 [M]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 601.0 [M+H]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 640.4 [M+Na]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 596.5 [M]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 665.1 [M+Na]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 671.0 [M+K]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 535.0 [M+H]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 549.0 [M+H]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 596.5 [M]+. 4.2 4 (c 0.5 CHCl3); 1H NMR (400 MHz DMSO-d6) 649.3 [M+K]+. 4.2 4 (c 0.5.