IR (KBr): : 3170, 2976, 2932, 2874, 1590, 1578, 1551, 1504, 1470, 1423, 1409, 1356, 1299, 1288, 1250, 1231, 1194, 1158, 1127, 1063, 1045, 1004, 924

IR (KBr): : 3170, 2976, 2932, 2874, 1590, 1578, 1551, 1504, 1470, 1423, 1409, 1356, 1299, 1288, 1250, 1231, 1194, 1158, 1127, 1063, 1045, 1004, 924.1HNMR (500 MHz, CD2Cl2): 7.60 (d, = 10.2 Hz, 1H), 7.40 (dt, = 19.9, 10.3 Hz, 2H), 7.13 C 7.02 (m, 3H), 6.97 (d, = 8.4 Hz, 1H), 4.33 (s, 4H). inhibition. The effects of tropolone were blocked by co-incubation with high levels of free extracellular iron but not by pre-loading with iron. Additionally, dose and time dependent reduction in ex (+)-Apogossypol vivo viability of cells from leukemia patients was observed. Taken together, we demonstrate that -substituted tropolones upregulate DNA damage repair pathways leading to caspase-dependent apoptosis in malignant lymphocytes. activity of purified metalloenzymes that regulate epigenetic modifications including histone deacetylases [23] and sirtuins [24]. (+)-Apogossypol However, the biological activity of tropolones is not well-understood and the importance of their metalloenzyme inhibition to the cellular mechanism of action is unclear. Likewise, while the -substituted natural products and their synthetic analogs are inhibitors of human cancer cell growth, less is known about their -substituted analogs. Our underlying hypothesis is usually that -substituted tropolones will function as potent and specific anti-leukemia brokers. Here, we evaluate the ability of -substituted tropolones including 2-hydroxy-7-(naphthalen-2-yl)cyclohepta-2,4,6-trien-1-one (-naphthyl tropolone) and its novel counterpart 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-hydroxycyclohepta-2,4,6-trien-1-one (-benzodioxinyl tropolone) to inhibit leukemia cell proliferation and induce apoptosis. Materials and Methods Test compounds The -naphthyl tropolone was synthesized as previously described [23]. The -benzodioxinyl tropolone was synthesized as follows. Tropolone (3.24 mmol) was dissolved in 16 mL acetonitrile and allowed to react with MeI (16.2 mmol) in the presence of K2CO3 (9.72 mmol) and 18-crown-6 (0.324 mmol) for 18 hours at 85 C to form the tropolone methyl ether. The mixture was cooled and filtered through a fritted funnel. The filtrate was evaporated to dryness, re-dissolved in dichloromethane and washed with base and brine. The organic layer was then evaporated to dryness and analyzed by NMR for purity. The methyl ether (1.87 mmol) was dissolved in 9.3 mL carbon tetrachloride and allowed to react with NBS (1.05 eq) for 2 hours at 80 C, forming the -bromo tropolone methyl ether. The mixture was cooled and filtered through a fritted funnel. The solid was washed several times with dichloromethane and the filtrate was evaporated to dryness. The sample was then re-dissolved in dichloromethane and washed (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography of the crude residue (SiO2, EtOAc in hexanes) provided the desired compound. Suzuki coupling was performed between the -bromo tropolone methyl ether (0.5 mmol) and 1,4-benzodioxane-6-boronic acid (0.75 mmol) (1.5 eq) to give the alpha-benzodioxinyl tropolone methyl ether. The coupling was performed in 1.7 mL dioxane and 0.16 mL water made up of cesium carbonate (3.0 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.1 eq) that had been degassed with argon and was allowed to proceed at 90 C for 18 hours. Water was added and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography of the crude residue (SiO2, EtOAc in hexanes) provided the desired (+)-Apogossypol compound. The methyl ether (0.36 mmol) was hydrolyzed in the presence of lithium chloride (3 eq) at 120C for 2-3 hours. The alpha-benzodioxinyl tropolone acid was purified by C-18 column chromatography. The crude product was added to the column in 4:1 water: methanol and eluted with 50% Itga2b methanol in water. Overall yield: 64%. Rf = 0.42 (1:1 EtOAc: hexanes). Mp = 102.8-103.6. IR (KBr): : 3170, 2976, 2932, 2874, 1590, 1578, 1551, 1504, 1470, 1423, 1409, 1356, 1299, 1288, 1250, 1231, 1194, 1158, (+)-Apogossypol 1127, 1063,.