Kinamycin

1. Discovery, producing organism and structures1-7)
Kinamycins were found from the culture broth of the actinomycete strain KA-295 and recognized as antimicrobial substances active against Gram-positive bacteria. The proposed structure
was revised by Gould et al.7) The first total synthesis of kinamycin C was achieved by John Jr. etal.9) and biosynthesis of kinamycin was achieved by Gould et al.12-17)

O

HOOR3

R4O

O

CH3–
N+N

OR2
OR1R1R2Kinamycin AH

COCH3BH

COCH3CCOCH3H

COCH3 COCH3DCOCH3H

COCH3

Streptomyces murayamaensis KA-295
Bar: 5 µm

R3R4

COCH3 COCH3HHH

2. Physical data (Kinamycin A)1)
Yellow needles. C25H23N2O10; mol wt 497.13. Sol. in MeOH, CHCl3, EtOAc. Insol. in hexane,
H2O.
3. Biological activity1,18)
1) Antimicrobial activity of kinamycins A, B, C, and D
MIC (µg/ml)
Test organism
Bacillus subtilis PCI219
Bacillus anthracis
Staphylococcus aureus FDA209P
Staphylococcus albus
Mycobacterium smegmatis ATCC 607
Escherichia coli NIHJ
Vibrio comma
Vibrio comma Inaba 904
Klebsiella pneumoniae
Salmonella typhosa 901 W
Shigella dysenteriae
Proteus vulgaris OX-19
Neisseria gonorrhoeae

AB

0.024
0.012
0.19
0.012
0.78
0.012
0.024
0.012
25
6.25>100
3.12>1000.19
500.09>100
12.5>100
6.25>10025>100
12.5>50>12.5

C
0.19
0.19
0.78
0.39
6.25
10025
 	100>100>100>100>100

D
0.012
0.024
0.024
0.024
6.25
12.5
12.5
25
12.5
25
6.25>50

2) Cell growth inhibition8,10,11)
Both kinamycin A and kinamycin C strongly inhibited cell growth of CHO cells.
Kinamycin A was the more potent of the two compounds and with a 72-h drug treatment the IC50
was in the low nanomolar range. The growth inhibitory effects of both these compounds werestrong even with drug exposure times of 1 h or less. Assuming that the compounds were washed
out of the cells, these results suggest that both kinamycin A and kinamycin C acted quickly on
their cellular targets to inhibit cell growth.
3) Cell cycle8,10)
Experiments were carried out on CHO cells synchronized through serum atarvation (normal doubling time of 12 h) to determine whether kinamycin A exerted a cell cycle block. The untreatedcells were still highly synchronized 5 h after serum reletion as evidenced by the low levels of Sand G2/M phase cells4) Inhibit topoisomerase II catalytic activity8,10)
Kinamycin A and kinamycin C inhibited the activity of topoisomerase II α. Kinamycin F inhibited the decatenation activity of human topoisomerase II α with an IC50 of 0.85±0.26 μ M
4. References
1. [40] T. Hata et al., J. Antibiot. 24, 353-359 (1971)
2. [60] S. Ōmura et al., Chem. Pharm. Bull. 21, 931-940 (1973)
3. [43] S. Ōmura et al., Chem. Pharm. Bull. 19, 2428-2430 (1971)
4. [32] S. Ito et al., J. Antibiot. 23, 315-317 (1970)
5. [56] A. Furusaki et al., Israel J. Chem. 10, 173-187 (1972)
6. [113] K. Ajisaka et al., J. Chem. Soc., Chem. Commun. 43, 571-572 (1976)
7.		
S. J. Gould et al., J. Am. Chem. Soc. 116, 2207-2208 (1994)
8.		
B. B. Hasinoff et al., Free Radical Biology & Medicine 43, 1132-1144 (2007)
9.		
A. John Jr. et al., J. Am. Chem. Soc. 128, 14790-14791 (2006)
10.		
G. I. Dmitrienko et al., Anti-Cancer Drugs 17, 825-837 (2006)
11.		
C. Melander et al., Biorg. Med. Chem. Lett. 16, 5148-5151 (2006)
12.		
S. J. Gould et al., Tetrahedron Lett. 26, 4023-4026 (1985)
13.		
S. J. Gould et al., J. Am. Chem. Soc. 108, 4625-4631 (1986)
14.		
D. E. Cane, Chemt.: Org. Chem. 1(1), 54-56 (1988)
15.
S. J. Gould et al., J. Org. Chem. 62, 320-324 (1997)
16.
S. J. Gould, Chem. Rev. 97, 2499-2509 (1997)
17.
S. J. Gould et al., J. Antibiot. 51, 50-57 (1998)
18.
M. K. Kharel et al., Nat. Prod. Rep. 29, 264-325 (2012)