acid analogs were dissolved i i i sterile water aiid added aseptically t o the previously autoclaved assay tubes. 111 all assays the amount of growth was determined photometrically a t 623 mp with a Bausch atid Lomb Spectroiiic 20 spectrophotometer, iii terms of absorbance readings of the turbid culture medium against
a blauk of iuiiiioculated medium set :E zero absorbiiiice. For E . coli the dat,a iii Table I are recorded as absorbance readitiga which are related to the milligrarns of dry cells calculat,ed from a ataiidard curve of milligrams of dry cells per milliliter us. absorbaiice readings.
Lincomycin. VI. 4'-Alkyl Analogs of Lincomycin. Relationship between Structure and Antibacterial Activity1 BARSEYJ. ~ I A G E R L EROBERT IS, D. BIRKEKMETER, ,4XD FREDK A G A K Tht Reaeurch Luboiutorits, 2'he Cpjohn Coinpuny, Kalutiiumo, J i ~ c h i y u n R e ~ e i ~ eJunuui d y 8, 1967
Thc partial hyiithesin of a herie:, of 4'-:ilkyl atlalogs of IiliconiyCtiii aiid l'-dcn~ethyl-l'-ethylliticoriiyciii is 1.eported. The in vitro ailtibacterial activity of some of these compoiiiitls was three to four times that of liiiconiyciii. Replac~eInetitof the i-hydroxyl group of these compoluids by chloriiie further enhanced the aiitibacterial activity. lielatioilships are drawn b e b e e n structure and in vilro aiid in vivo antibacterial activity.
Lincbomycin, a water-soluble antibiotic,2 is orally effective in man for the treatment of diseases caused by gram-positive orga~iisms.~ The elucidation of the structure of lincomycin (1) showed that it was not chemically related to any of the major antibiotic^.^ Lincomycin may be cleaved into an amino acid fragnietit, 2, ans-1-methyl-4-n-propyl-L-proline(2) and an amino sugar, methyl thiolincosamiiiide (3). These fragments may be recombined to yield liiicomycin by employing one of the standard methods for amide formation.; The unique chemical stability of liiicomycirl
O C3H7-n C O O H
1
2
scribed partial synthesis of The synthetic scheme is outlined in Chart I. 1-CarbobenzCH.'dLI'
1
?
c 5
/
6
3
arid the cleava~e-reconibiiiatiorl sequence established the antibiotic as a highly desirable substrate in which t o study t'he effect of chemical modification on antibacterial activity. The synthesis arid ant'ibacterial properties of liticomyciii analogs having various alkyl groups ut N-1' arid C-4', arid in some cases having the 7-hydrosyl replaced by chlorine, are now described. The met'hod for preparat'ion of 4'-alliyl arialogs of liticomycin \vas a modification of the previously de(1) .\ portion of this work was reported earlier, Abstracts of Papers, Vtli Interscience Conference on .intimicrohial Agents and Chemotherapy and IVth International Congress of Cliemotlierapy, IVasIiington, D. C., Oct 1711,1965, p 17. ( 2 ) la) D. ,I. Mason. .I. Dietz. and C. D e l h e r in ".\ntiinicrol)ial .\gent5 and C'liernotlierapy-1Y62." J. C. Sylyester, Ed., .\merican Society for ;IIicrol)ioloey, .Inn .\rl)or, Micli., lY6'3, p 554: (11) R. R. Herr and AI, E. 11 5 8 0 ; (c) C . Lewis, H. \\-, Clapp. and J. E. Grady. h i d . , p 5 i O . lincomycin hydrochloride. ( 3 ) (a) JV. J. Holloway, R. H. Kahlbaugh, and E. G. Scott in ".intimicrobial Agents and Chemotherapy-1963," J. C. Sylvester, Ed., American Societv f o r Microbiology, Ann h r h o r , Mich.. 1964, p 200; (b) ,I. Harnecker, .J. Contrrras, 13. Gilabert, and V. Uhilla, ibid., p 204: ( c ) E. \V. \ValterR, hI. .I. Romansky. and .\. C. .Jotinson, i b i d . , p 210; (d) .J. C. Trakas and 11. E. Tind, i b i d . , 1' 216. (4) II. Hoeksema. 11. Ijannister, R. D. Ijirkenmeyer, F. Iiagan, 13. J. llagerlein, F. .\. lIacKellar, I T . Schroeder. G. Sloinp, and R . R . Herr, J . A m . Chern. S o c . , 8 6 , 4229 (1964). ( 3 ) \V. Scliroeder, D . Uannister, and H. Hoekaeina, %bid., in press.
8
' /
J,
10
9
R'
MTL= HO SMe
SMe
OH
K=alkyl substituent
OH 11
( 6 ) 13. J. blagerlein. R . 1). Birkenmeser. R. R . Herr, and F. Kayan,
in preas.
ihirl.,
~
Yield,
,,
R
n-CaH, TL-C~T~ n-C:JIlI n-CiHl; n-CI;IT,:
46.8 40 . .i 38. 0 43.4 3 1. 0
.
-
C '
'
