COMMUNICATIONS TO THE EDITOR
Oct., 1947
2567
The purified product was obtained crystalline Since the yield of 6-tetrahydroxypteriiie by the above procedure was small, our attention was as clusters of yellow needles, and in 0.1 N sodium centered on the more direct synthesis of I11 by the hydroxide solution it shows ultraviolet absorption condensation of I with osones (11). The reaction maxima a t 260, 284 and 370 mp, and minima a t of I with I1 is rapid and yields I11 in good quan- 239, 271 and 333 mp. Anal. Calcd. for CI9H2,tity. The conditions for obtaining the preferred 0&8.2H20: C, 47.9; H, 5.1; N, 23.5. Found: isomer appear to be reversed from that described C, 47.:3; H, 5.15; N, 23.4. Magnesium salt: * ~44.2; H ~ O :H, above-;. e., I and I1 a t p H 5-9 yield the 6-isomer, Calcd. for C I ~ H ~ E O ~ N E M ~C, while the condensation of I-bisulfite and I1 in 4.T; N, 21.7; Mg, 4.7. Found: C, 44.6; H, strongly acidic solution yields a mixture richer in 4.%; N , 21.4; Mg, 4.82. The biological properties have been examined by Dr. B. L. Hutchings the 7-isomer. Although details of work on pure isomers will and Dr. E. L. K. Stokstad of the Lederle Laborabe published later it is deemed worthy to report tories Division, American Cyanamid Company, the synthesis oF the isomeric mixture of I11 and Pearl River, New York. The inhibition ratio for the preparation of the isomeric mixture of formyl- half-maximum inhibition of the growth of Strepfosoc~irsfuecalis R is 1.9, 0.7 and 0.4 a t concenpterine (IV) from I11 by the method outlined. D-Glucosone was heated with an eqnivaleiit trations of pteroylglutamic acid of 0.003, 0.005 amount of “4,3-triainiiio-Ci-hydroxypyrimiditie ~ i i d0.01 microgram per 10 ml., respectively. Details of the synthesis and properties of this bisulfite in 7tjf( acetic acid a t 73” for forty-five minutes. The mixture was cooled and the pre- and related compounds will be the subject of subcipitate collected. The product was exhaustively sequent communications. extracted with hot alcohol aiid dried. Yield of Car co CHEMICAL DIVISION DORISR. SEEGER ~) (169.2 mg. per 100 ~ I E R I C A YC Y A Y a M I D c O M P A \ Y JAMES M. S M I T H , JR. 111 was 6Oz,,[ c x ] ~ ‘ ~-70.9’ JERSEY XARTIS E. HULTQUIST ml. of -IrNaOH). Absorption spectrum in 0.1 -V 1 3 0 ~VI-, BROOK,SEW RECEIVEDSEPTEMBER 19, 1947 KaOH showed maxima a t 232 mp and 360-362 nip with e of 19,000 and 7940, respectively. Anal. Calcd. for C10H13N606: C, 42.39; H, BIOSYNTHESES INVOLVING PANTOTHENIC AClD 1.62; N, 24.71. Fourid: C, 42.1:; H, 4.(12; N Sir : (Kjeldahl), 25.11. In Esdherichitc soli cysteic acid appears to preI11 was oxidized with lead tetraacetate to IV, vent competitively the decarboxylation of aspartic a n isomeric mixture, obtained in S3yGyield. IV acid to @-alaninewhich results in pantothenic acid contained ash which was hard to remove. It ex- becoming a limiting growth factor.’ Under our hibited strong carbonyl activity forming oximes, testing conditions the rate of pantothenic acid hydrazones and Schiff bases readily. IV treated synthesis is determined by the ratio of cysteic to with a slight excess of barium permanganate gives aspartic acid, and exogenous substances allowing Y,identity of which was established by its ultra- growth to occur a t a lower rate of pantothenic violet absorption, titration curve and analysis. acid synthesis produce an increased antibacterial Anal. Calcd. for C7H6N6o2H20: C , 40.2; index. K , 33.5. Found: C, 38.8; N (Kjeldahl), 31.5 Such an effect is obtained with citric, cis(cor. for 4.90% ash). aconitic or a-ketoglutaric acids. The antibac . H. G. PETERINGterial index over a thirty-fold range in aspartic THEUPJOHXCOMPANY KALAMAZOO, MICHIGAN D. I. WEISBLAT acid concentrations was 300 in the medium conRECEIVED AUGUST18, 1947 taining these substances but only 30 in their absence. Oxalacetic and pyruvic acid were inactive alone, but a mixture of both necessitated a slight ANTAGONIST FOR PTEROYLGLUTAMIC ACID increase in the concentration of cysteic acid to obSir: tain the same growth inhibition. Acetate alone \Ve wish to report the synthesis of a potent possessed some activity. Pantoic acid was inacpteroylglutamic acid antagonist, N- [4-{ [ (2,4-d1- tive. The apparent “sparing action” of cisamino - 6 - pteridyl) - methyl] - amino] - benzoyll- aconitic acid on the pantothenic acid requireglutamic acid. In the course of an investigation ment of E . coli is not equaled by its precursors; of analogs of ptieroylglutamic acid, this compound hence, it appears that pantothenic acid deficient was prepared from 2,4,5,6-tetraminopyrimidine cells are unable to convert effectively pyruvate sulfate,’ 2,3-d1bromopropionaldehyde, and p - and oxalacetate to cis-aconitate (or ketoglutarate). aminobenzoylglutamic acid under the conditions This datum explains the previously reported’ described for the synthesis of pteroylglutamic enhanced activity of glutamic over aspartic acid acid.2 Purification of the crude product was ac- in preventing the toxicity of cysteic acid. The complished by a method very similar to that used transamination reaction produces both aspartic for pteroylglutamic acid.3 and a-ketoglutaric acids, the latter having a ( 1 ) Traube Ber ( 2 ) Angler rl ni (31 Vvaller el al
37, 4545 (1904) Sctence 103, 667 (1946) ’IHIS J O U R N A L 69, In Dress (1947)
(1) Ravel a n d Shive, J Bid Chem., 166, 407 (1946). (2) Molar ratio ( a n a l o g t o metabolite) just n e c e s s a r y for maximum inhibitiuu of growth.
