Synthesis of Potential Antineoplastic -Agents. XXXIII. p-Diketone Analogs of the Glutarimide Antibiotics'
Tlic structures of cyclohesiiiiide? (I, R = €I), E-7:.j3 (an antitumor substaiice from Strzptomyces albulus, I, R = OCOCH,). streptovitaciii .A4 (I, R = OH), streptimidoiie,j iiiactoiie,6 and t,lie other strcptovitaciiis.' have glutariiiiide and 8-keto1 iiioic:ties, a i d the first three of these gliitariiiiidc aiitibiotics are reported to iiihibit the growth of esperiiiiciital iieoplasiiis.' Of additioiial sigriificaiice to c m c w cheiiiotherapy is t htl iiihihitory action of cyclohesiiiiide 011 deosyriboiiucleic acid arid protein synthesis iii certaiii tunior cell lines.8 These biological results indicated that aiialogs of tlic glutariniide antibiotics iiiay c w r t aiititunior df'ect$. n'c have synthesized tlirw gimps of glutariiiiide antibiotic analogs iii ivhich the P-keto1 grouping is replacctl 1)y the P-diketone group of tlchydro derivatives such as deliydroc~cloliesiiiiide?(IIj. The first group (Y) coilsists of derivatives iii whicli the degree of substitution of the cyclohexanone riiig of' cyclohesiiiiide and E:-73 has bcteii varied. ,Iinoiig the cwiiipouiids of t h e secoiicl g o u p (\-I), these structural variatioiis arr coid)iiicttl ivith a shorteiiiiig of the side cliaiii hy c3liiiiinatioii of the iiicthylene groiip, and i i i thcb third group (1-11:).thc. stiuctural variatioiis o f the oyclohesniioiie g i ~ aq w cciii1)iiied with thc replaceiiiciit of thc glutariinide riiig 1)s the succiiiiiiiide ring. T h e d-diketoiie analogs (\--\TI j were synthesized by tlie iiiodifiedg eiia.iiiiiic acylation iiiethod of Stork, el ( L L . , ~ Ofroiii an appropriately substituted eiiaiiiiiie (Il-) aiitl a carbosylic acid chloride (111) in tlic piwenee o t triethylaniiiit.. Tlic eiiaiiiiiies were plep:ircd by tlic ( 1 ) T i i i . iiirestigativil \vas s u p p u r t e t l ljy tlir C'uncer ('lieiiiotlier.ai~y S i t Jervire Center, S a t i u n a l Cnrwer Institute, Kational I n s t i t u t r a of
tioii:il
llealth. Contract No, PfI-43-61-51, and by t h e C. 1.~. Ilettering l'oundstiori. I m . Chem. SOC.,Ii, 130 (2i I:. C. Kornfel~l,13. G. Jones, T. V. I'nrke ( 19.1~l~.
( 3 ) Iure. Evaporation of the reaction mixture in t'ucuo with mild heating produced a sirup which was hydrolyzed a t 0" with 6 &Vhydrochloric. arid. The p-diketone was obtained by extraction of the aqueous system with t,hree50-nil. portions of ether, neutralization of the aqueous layer, extraction with t,hree 50-nil. portions of ether, then with ethyl acetate (50 nil.), evaporation of the ethyl acetate and the combined et,her extracts separately, and trituration of the two residues in ethanol. From the et,her ext,ract was obtained 375 nig. of crude product, from the et,hyl acetate extract, 210 nig. Crystallization of the crude product from ethanol gave 400 mg. (105;) of solid, n1.p. 170-173". The analytical sample x a s obtained by crystallization (charcoal decolorization) from ethanol, m.p. 175', 295 mu. Anal. Calcd. for Cl2HljSO4: C, 60.77; H, 6.3X; S , 5.90. Found: C, 60.71; H, 6.25; S , 5.88. ilnother experiment, analogous to the preparation of 1 l a except that, the reaction mixture was stirred for 3.5 hr. a t room temperature after the triethylamine addition and allowed to stand 5 hr. instead of overnight, gave a different product. After removal of the volatile components in uaci(o, the mixture was poured into water and stirred for 5 min. A solid (3.1 9.) was collected by filtration and was purified by washing with hot ethanol and crystallizing from ethanol-dimethylformamide, and then from ethanol. Analyses of the product (1n.p. 220" a i t h decomposition) Iwre consistent with structure I X . ilnal. Calcd. for I X (C2&&306): C, 62.30; H, 6.58; S , 9.46. Found: C, 62.04; H, 6.67; X, 9.40. 3-(5-Methyl-2-oxocyclohexylcarbonyl)glutarimide(VIb) was obtained from 4-methyl-1-piperidinocyclohexene (3.1 g., 17 mmoles), 3-(chlorocarbongl)glutariniide (2.8 g., 16 mmoles), and triethylamine ( 5 nil.) in dimethylforniamide by a procedure analogous to that used in the preparation of VIa. The crude product, obtained by trituration of the ether and the ethyl acet,ate extract residues in ethanol, was crystallized from ethanol; yield, 520 mg. (13yi); m.p. 178": A,,,, ( n i p ) : a t pH 1,29X; at, pH 7 , 299; and a t pH 13, 319. Anal. Calcd. for ClaHliSO~:C, 62.13; H, 6.82; 1,5.58. Found: C, 62.14; H, 6.89; S , 5.58. I n a related, large-scale experiment, treatment of the acid chloride in diniethylformaniide with the enamine in dimethylformamide followed by adding triet,hylamine, stirring 4 days at' room temperature, evaporating the mixture to a sirup, and triturating in 3 .I- hydrochloric acid, gave a solid which was washed with hot ethanol and purified by crystallization from dimethylformamide-ether. Analyses of the product (n1.p. 229232' dec.) mere consistent with structure S . Anal. Calcd. for X (ClgH2&20i): C, 58.45; H, 5.68; S , 7.18. Found: C, 57.88; H, 5.56; N, 7.26. The yield, based on structure X, was 245;. I n addition, a 12yo yield of 1-Ib was isolated from the hydrochloric acid trituration filtrate. 3-(5-Acetoxy-2-oxocyclohexylcarbonyl)glutarimide(VIc) was obtained from 4-acetoxy-1-piperidinoc'yclohexene (3.8 g., 17 Inmoles), 3-( chlorocarbony1)glutarirnide (2.8 g., 16 mrnoles), and triet'hylamine (5 ml.) in dimetliylforrnamide by a procedure
Polypeptides from p-Phenylalanine Alus tardl
Iiiteiise interest in p-phenylalaniiie mustardL ( p m-colysiii,*I) in recciit yc'ars as ail aiiticaiicer drug has Ird to tlic prepai.ation aiid study of various aiialogs :uid dcrivativcs. i i i a search for eiihaiiccd aiiticauccr
