MeOH was refluxed for 4 hr and allowed to stand for 3 days. Water was added, and the mixt was extd with E g o . The Et20 soln was washed (dil HC1, dil NaHCO1, HzO, and satd NaCl) and dried (Na,SO,). After filtration and evaporation of the solvent, the product was distd giving 36.8 g of solid, bp 152" (0.1 mm). A sample was recrystallized from i-PrOH giving white crystals, mp 81-83". Anal. C, H, C1.2'Chlor*2-(o-chlorophenyl)-3-( 1-pyrrolidiny1)propiophenone Hydrochloride (21). A mixt of 35 g (0.126 mole) of 2'-chloro-2-(0-chloropheny1)acrylophenone and 12 ml(O.15 mole) of pyrrolidine was warmed to effect soln and allowed to stand for 4 days. The re sulting oil was dissolved in EtzO, washed (HzO, satd NaCl), and dried (NaS04). After filtration, the soh was acidified with ethanolic HCl, and the resulting solid was crystallized from EtCOMe yielding 19.6 g of white crystals, mp 135-1 36".4'Chloro-2-@-chlorophenyl)acrylophenone. This was prepd as described above for the ortho isomer from 10 g (0.0378 mole) of 4-cNoro-2-pchlorophenyl)acetophenone,'3 8.8 ml(O.11 mole) of 37% CH,O, and 0.19 ml of piperidine in 35 ml of MeOH. The product was not distilled but was recrystallized from hexane yielding 7.2 g (69%) of white crystals, mp 80-83". Anal. C, H, C1Benzyl Indol-3-yl Ketone. A soln of 287.6 g of N,N-dimethylphenylacetamide in 300 ml of PhH was cooled under N, to 10' and 108 ml of POCl, was added dropwise with stirring, After warming to 20°, 102.9 g (0.878 mole) of indole was slowly added keeping the temp below 48" by cooling. The mixt was then refluxed for 2 hr, cooled, and poured into 6 1. of H,O. A soh of 307.5 g of NaOH in 914 ml of H,O was added, and the mixt was stirred for 1 hr. The product was extd with Et,O, washed (H,O, satd NaCl), and evapd in vacuo. The residue was mixed with 200 g of NaOAc in 200 ml of H,O and 3 1. of MeOH, refluxed for 3 hr, and cooled to near 0". The solid was collected, washed (MeOH), and dried yielding 122.6 g of product, mp 206.5-209'. An addnl45.5 g (total 81.5%) was obtained by concn of the filtrate. A sample was recrystd from EtOAc, mp 208-209". Anal. C, H. N.-Method C. l-(Indol-3-yl)-2-phenyl-l-propenone and l-(IndoE3yl)-2-phenyl-3-( 1-piperidiny1)-1-propanone (29). A mixt (prepared under N, with cooling) of 50 ml of AcOH, 4.9 ml(O.05 mole) of piperidine, 11.76 g (0.05 mole) of benzyl indol-3-yl ketone, and 2 g (0.0666 mole) of paraformaldehyde was stirred at 100-110" for 3-5 hr, cooled, and concd in vacuo to half its vol. This was poured into ice water and the solid was collected, washed (H,O), and dried giving 4.68 g of l-(indol-3-yl)-2-phenyl-l-propenone, mp 175-181S0. Recrystallization from EtOAc-hexane gave 1.17 g of crystals, mp 195-196.5'. Anal. C, H, N.The aqueous filtrate was basified with NaOH giving free base which was collected, dried, and recrystallized from EtOAc yielding 8.99 g (54%) of 29, mp 171.5-172S0. Recrystallization from EtOAc-hexane raised the mp to 172.5-173.5'.l-(Indol-3-yl)-3-(4-methyll-piperazinyl)-2-phenyl-1-propanone (31). A mixt of 6.33 g (0.0266 mole...
A number of antineoplastic agents possess both the quinone nucleus and an appropriate substituent that permits them to function as bioreductive alkylating agents. To develop new compounds of this type with unique properties, we have synthesized a series of 2- and 6-methyl-1,4-naphthoquinone derivatives and have evaluated them for antineoplastic activity against Sarcoma 180 ascites cells. Several of these quinones showed antitumor activity, causing significant prolongation of the survival time of tumor-bearing mice. Among the most active agents were the mesylates, tosylates, and N-(chloroethyl)carbamates of 2- and 6-methyl-1,4-naphthoquinone. That bioreductive activation to a quinone methide might be involved in the mechanism of action of these agents was shown by the finding that compounds with the best leaving groups were the most efficacious as antineoplastic agents.
A series of 1,2-bis(sulfonyl)hydrazines was synthesized and evaluated for antineoplastic activity against the L1210 leukemia and the B16 melanoma. The most active agent to emerge from this study, 1,2-bis(methylsulfonyl)-1-methylhydrazine, produced a maximum % T/C for mice bearing the L1210 leukemia or the B16 melanoma of 340% and 278%, respectively. Two N-chloroethyl analogues, conceived as bifunctional alkylating agents, were also synthesized and evaluated for antineoplastic activity against the L1210 leukemia and the B16 melanoma. Although such a modification resulted in retention of antineoplastic activity against both tumor cell lines, it did not result in enhanced antineoplastic activity.
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