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Studies on the ionophorous antibiotics. Part III. The structure of lonomycin, a polyether antibiotic
TetrahedronLetters No. 47, pp 4147 - 4150, 1975. PergomonPress. Printed in Great Britain.
STUDIES ON THE IONOPHORCUS ANTIBIOTICS. PART III. THE STRUCTURE OF LONOMYCIN, A POLYETHER ANTIBIOTIC
Noboru &eke and Mitsuo Koenuma Institute of Applied Microbiology, The University of Tokyo Hiroshi Miysmae, Shoichi Sato and Yoshihiko Saito Institute for Solid State Physics, The University of Tokyo
(Receivedin Japan 17 September1975; receivedin UK for publication7 October 1975) Lonomycin')is an antibiotic elaborated by Streptomyces ribosidificus and shows an antimicrobial activity against gram-positive bacteria including mycobacteria as well as some kind of filsmentous fungi.
Lonomycin is also effective in the treatment of coccidial infections
in poultry and shows some chemical and biological characteristics common in the family of polyether antibiotics. In the course of our serial studies 2 93) on the ionophores, we have elucidated the entire structure of lonomycin as depicted in Fig. 1 using the thallium salt by a three dimensional X-ray analysis. The thallium salt of lonomycin crystallizes from methanol-water
in plates, m.p. 150.2-150.3'C
The molecular formula, Ct+1,H7s014Tlis confirmed by comparison with the formulae of the methyl ester, CssH7e01b(M+-HeO, m/e 824) and the sodium salt, CbsHvs01sNa(M+, m/e 850).
Crystal data:
orthorhombic, space group P212121, a=16.257(2), b=25.731(4) and c=12.502(2):, ti=1..36
(flotationin aqueous KI), Dc=1.33 g/cm3 for 24.
Fig. 1
The structure of lonomycin
4147
4148
lo.
47
The intensity data were collected on an automated four-circle diffractometer using MO Ka radiation
(X=O.?l.O7j;). The maximum value of 26 was 53' in the w-20 scan technique.
Since the
thallium salt of lonomycin decomposed gradually in the X-ray beam, four crystals were used and the intensities were corrected by comparison with the standard reflexions. The structure was solved by the heavy-atom method.
The positional and thermal parameters for
the non-hydrogen atoms were refined by the block-disgonal temperature factors.
least-squared method using anisotropic
The final R-value for the 3225 reflexions used in the refinement was 0.078.
The final coordinates and their standard deviations are given in Table 1.
Table 1.
Positional parameters for the non-hydrogen atoms (x 103), with their e.s.d.'s
Tl c(1)
O(2) O(3) O(4) O(5) O(6) c(7) O(8) O(9) O(10) O(11) O(12) O(13) O(14) O(15) O(l6) O(17) O(18) O(19) O(20) 0 (21) cc221 O(23) O(24) O(25) O(26) cc271 O(28) O(29)
X
Y
35(0 39(21
83 0 167Hl 206(i) 199(l) 235(l) 233(l) 244(l) 204(l)
71(l) 170(2) 202(2) 300(2) 32'+(2) 287(i) 307(2) 255(l) 233(2) 184(2) 225(2) 264(l) 328(2) 326(l) 237(l) 188(2) 174(2) 96(2) 60(l) -32(2) -96(2) -173(2) -135(l) -l69(1) -260(2) -298(l) -278(l) -183(2)
211(l)
177(l) 202(l) 162(i) 109(l) 86(l) 48(l) 18(l) 25(l) -26(i) -45(l) -80(1) -64(l) -46(l) -90(l) -53(l) -10(l) 45(l) 45(l) 95(l) 100(l) 100(l)
in parentheses
X
-18(o) -209(2) -288(2) -300(2) I$;;;;
O(30) c(31) O(32) c(33) O(34) cc351
1:g] -65(3)
:I;,",' ~(38)
98(2) -5(3) -43(3) -32(2) 82(3) 73(3) -43(2) I",;$ -14(3) $1:; 65(2) 15(3) -99(2) -115(2)
:I:;; c(41) C(42) cc431 c(44) O(1) o(2) O(3) O(4) O(5) o(6) 0i7j
o(8) O(9) O(10) o(n) O(12) O(13) O(14)
-156(2) 44(2) l78(2) E',Ej 397(2) 3:21z; 237(2) 6-f(2) -82(2) I;;;# -318(2) -"%:i -7(l) 196(l) :,":11'; 302(l) 101(l) 201(l) 104(l) -45(l) I:;:;:;
Z
Y
103(l)
261(i) 223(l) 301(l) 263(l) 207(l) 220(l) %I:; -106(l) -130(l) -108(l) 45(l) :z;t:; 121(l) 183(l) 211(l) 148(l) 269(l) 128(i) 154(l) 64(l) -19(l) -12(l) -::I:; 92(l) 144(l)
-229(2) -264(3) I:;$, -475(4) ;:44tz; 144(4) -l64(2) -127(3) 69(3) -17(4) l86(3) -% I::$; -197(l) :;;60$ 23(l) 132(2) 25(2! -78(l) 44(l) 49(l) -71(l) 28(2) -53(2)
The absolute configuration was determined by use of the anomalous dispersion effect of the thallium atom for MO Km radiation.
Differences between intensities of some reflexions and those
of their counter-reflexions were clearly discernible as shown in Table 2.
Determination of absolute configuration of lonomycin
Table 2.
hk
1
Fo(hkl)
Fc(hkl)
Fo(Gl)
Fc(dl)
141
52
45
66
61
112
23
31
40
47
122
109
104
165
163
19
2
57
50
44
43
110
3
46
37
36
27
117
5
66
72
54
57
14
6
76
87
90
105
57
57
47
43
117 111
7
83
80
70
70
114
7
56
55
38
44
54
45
1
310
74
52
The resulting molecular structure of lonomycin thallium salt viewed along the c axis is illustrated in Fig. 2 which correctly represents the absolute configuration of the antibiotic. The whole molecule takes a circular conformation and the thallium (I) ion is located in a cavity The thallium atom co-ordinates to six oxygen atoms in the distance ranging from 2.6 to 3.0:. The structure of lonomycin is similar tothosefound
for nigericin') and grisorixin'),
however, it differs in the conformation of ring F and the side chain bearing the carboxylic function.
4150
lb. 47
Fig. 2
The molecular structure of lonomycin viewed along the c-axis
Acknowledgement We are grateful to Prof. H. Yonehara of the Institute of Applied Microbiology for his interest and discussions through this work and to Drs. S. &m-a, Pharmaceutical
Co. Ltd. for the supply of lonomycin.
J. Sawada and I. Tanaka of Taisho This work was supported in pert by a grant
Prom the Ministry of Education, Science and Culture, the Government of Japan.
References 1) S. &mu-a, S. Machida, J. Sawada, I. Tanaka and N. &x&e, Of The Agricultural Chemical Society, Japan. 2) H. Kinashi, N. &xke,
Abstract Papers of the Annual Meeting
page 84, Sapporo, 1975.
H. Yonehera, S. Sato end Y. Saito, Tetrahed. Letters
4955 (1973)
3) N. Btake, M. Koenuma, H. Kinashi, S. Sate and Y. Saito, Chem. Comm. 92 (1975) 4) L. K. Steinrauf, M. Pinkerton and J. W. Chamberlin, Bipchem. Biophys. Res. Comm. -33 29 (1968) 5) M. Alleaume and D. Hickel, Chem. Comm. 1422 (1970)
STUDIES ON THE IONOPHORCUS ANTIBIOTICS. PART III. THE STRUCTURE OF LONOMYCIN, A POLYETHER ANTIBIOTIC
Noboru &eke and Mitsuo Koenuma Institute of Applied Microbiology, The University of Tokyo Hiroshi Miysmae, Shoichi Sato and Yoshihiko Saito Institute for Solid State Physics, The University of Tokyo
(Receivedin Japan 17 September1975; receivedin UK for publication7 October 1975) Lonomycin')is an antibiotic elaborated by Streptomyces ribosidificus and shows an antimicrobial activity against gram-positive bacteria including mycobacteria as well as some kind of filsmentous fungi.
Lonomycin is also effective in the treatment of coccidial infections
in poultry and shows some chemical and biological characteristics common in the family of polyether antibiotics. In the course of our serial studies 2 93) on the ionophores, we have elucidated the entire structure of lonomycin as depicted in Fig. 1 using the thallium salt by a three dimensional X-ray analysis. The thallium salt of lonomycin crystallizes from methanol-water
in plates, m.p. 150.2-150.3'C
The molecular formula, Ct+1,H7s014Tlis confirmed by comparison with the formulae of the methyl ester, CssH7e01b(M+-HeO, m/e 824) and the sodium salt, CbsHvs01sNa(M+, m/e 850).
Crystal data:
orthorhombic, space group P212121, a=16.257(2), b=25.731(4) and c=12.502(2):, ti=1..36
(flotationin aqueous KI), Dc=1.33 g/cm3 for 24.
Fig. 1
The structure of lonomycin
4147
4148
lo.
47
The intensity data were collected on an automated four-circle diffractometer using MO Ka radiation
(X=O.?l.O7j;). The maximum value of 26 was 53' in the w-20 scan technique.
Since the
thallium salt of lonomycin decomposed gradually in the X-ray beam, four crystals were used and the intensities were corrected by comparison with the standard reflexions. The structure was solved by the heavy-atom method.
The positional and thermal parameters for
the non-hydrogen atoms were refined by the block-disgonal temperature factors.
least-squared method using anisotropic
The final R-value for the 3225 reflexions used in the refinement was 0.078.
The final coordinates and their standard deviations are given in Table 1.
Table 1.
Positional parameters for the non-hydrogen atoms (x 103), with their e.s.d.'s
Tl c(1)
O(2) O(3) O(4) O(5) O(6) c(7) O(8) O(9) O(10) O(11) O(12) O(13) O(14) O(15) O(l6) O(17) O(18) O(19) O(20) 0 (21) cc221 O(23) O(24) O(25) O(26) cc271 O(28) O(29)
X
Y
35(0 39(21
83 0 167Hl 206(i) 199(l) 235(l) 233(l) 244(l) 204(l)
71(l) 170(2) 202(2) 300(2) 32'+(2) 287(i) 307(2) 255(l) 233(2) 184(2) 225(2) 264(l) 328(2) 326(l) 237(l) 188(2) 174(2) 96(2) 60(l) -32(2) -96(2) -173(2) -135(l) -l69(1) -260(2) -298(l) -278(l) -183(2)
211(l)
177(l) 202(l) 162(i) 109(l) 86(l) 48(l) 18(l) 25(l) -26(i) -45(l) -80(1) -64(l) -46(l) -90(l) -53(l) -10(l) 45(l) 45(l) 95(l) 100(l) 100(l)
in parentheses
X
-18(o) -209(2) -288(2) -300(2) I$;;;;
O(30) c(31) O(32) c(33) O(34) cc351
1:g] -65(3)
:I;,",' ~(38)
98(2) -5(3) -43(3) -32(2) 82(3) 73(3) -43(2) I",;$ -14(3) $1:; 65(2) 15(3) -99(2) -115(2)
:I:;; c(41) C(42) cc431 c(44) O(1) o(2) O(3) O(4) O(5) o(6) 0i7j
o(8) O(9) O(10) o(n) O(12) O(13) O(14)
-156(2) 44(2) l78(2) E',Ej 397(2) 3:21z; 237(2) 6-f(2) -82(2) I;;;# -318(2) -"%:i -7(l) 196(l) :,":11'; 302(l) 101(l) 201(l) 104(l) -45(l) I:;:;:;
Z
Y
103(l)
261(i) 223(l) 301(l) 263(l) 207(l) 220(l) %I:; -106(l) -130(l) -108(l) 45(l) :z;t:; 121(l) 183(l) 211(l) 148(l) 269(l) 128(i) 154(l) 64(l) -19(l) -12(l) -::I:; 92(l) 144(l)
-229(2) -264(3) I:;$, -475(4) ;:44tz; 144(4) -l64(2) -127(3) 69(3) -17(4) l86(3) -% I::$; -197(l) :;;60$ 23(l) 132(2) 25(2! -78(l) 44(l) 49(l) -71(l) 28(2) -53(2)
The absolute configuration was determined by use of the anomalous dispersion effect of the thallium atom for MO Km radiation.
Differences between intensities of some reflexions and those
of their counter-reflexions were clearly discernible as shown in Table 2.
Determination of absolute configuration of lonomycin
Table 2.
hk
1
Fo(hkl)
Fc(hkl)
Fo(Gl)
Fc(dl)
141
52
45
66
61
112
23
31
40
47
122
109
104
165
163
19
2
57
50
44
43
110
3
46
37
36
27
117
5
66
72
54
57
14
6
76
87
90
105
57
57
47
43
117 111
7
83
80
70
70
114
7
56
55
38
44
54
45
1
310
74
52
The resulting molecular structure of lonomycin thallium salt viewed along the c axis is illustrated in Fig. 2 which correctly represents the absolute configuration of the antibiotic. The whole molecule takes a circular conformation and the thallium (I) ion is located in a cavity The thallium atom co-ordinates to six oxygen atoms in the distance ranging from 2.6 to 3.0:. The structure of lonomycin is similar tothosefound
for nigericin') and grisorixin'),
however, it differs in the conformation of ring F and the side chain bearing the carboxylic function.
4150
lb. 47
Fig. 2
The molecular structure of lonomycin viewed along the c-axis
Acknowledgement We are grateful to Prof. H. Yonehara of the Institute of Applied Microbiology for his interest and discussions through this work and to Drs. S. &m-a, Pharmaceutical
Co. Ltd. for the supply of lonomycin.
J. Sawada and I. Tanaka of Taisho This work was supported in pert by a grant
Prom the Ministry of Education, Science and Culture, the Government of Japan.
References 1) S. &mu-a, S. Machida, J. Sawada, I. Tanaka and N. &x&e, Of The Agricultural Chemical Society, Japan. 2) H. Kinashi, N. &xke,
Abstract Papers of the Annual Meeting
page 84, Sapporo, 1975.
H. Yonehera, S. Sato end Y. Saito, Tetrahed. Letters
4955 (1973)
3) N. Btake, M. Koenuma, H. Kinashi, S. Sate and Y. Saito, Chem. Comm. 92 (1975) 4) L. K. Steinrauf, M. Pinkerton and J. W. Chamberlin, Bipchem. Biophys. Res. Comm. -33 29 (1968) 5) M. Alleaume and D. Hickel, Chem. Comm. 1422 (1970)