Trienomycin

1. Discovery, producing organism and structures1-7)
Trienomycins were isolated and identified as antitumor antibiotics from the culture broth of theactinomycete strain 83-16. The stereostructures of trienomycins were elucidated by a chemical
synthetic method4,6,7). The first paper on the total synthesis of trienomycins A and B, C and F has
been reported by Smith et al.8,9) (See Appendix-I).

Streptomyces sp. 83-16

2. Physical data (Trienomycin A)1)
Colorless powder. C36H50N2O7; mol wt 622.36. Sol. in MeOH, EtOH, acetone, EtOAc, BuOAc,
CHCl3, CH2Cl2, THF. Insol. in H2O, hexane.
3. Biological activity10,11)
1) Cytocidal activity10)

Trienomycin
ABC
DE*: MIC,

NT: not tested.

IC50 (µg/ml)
HeLa S3
0.005
0.2
0.1
0.022*
0.104*

P388

0.02
1.6
0.1NTNT2) Antitumor activity of trienomycin A11)
Sarcoma 180

P388 leukemia

IMC carcinoma

Dose(mg/kg)

MSD

ILS (%)MSD

ILS (%)MSD

ILS (%)

Saline32 X 10
16 X 108 X 10
4 X 1010.1 ± 0.8
22.8 ± 3.9*
24.8 ± 3.4*22.4 ± 5.9*
13.0 ± 1.8*

0 		128		148		124		0		

10.4 ± 0.5
18.2 ± 2.3*
17.0 ± 2.2*
15.2 ± 1.1*
13.6 ± 0.5*0 		75		
64		46		31		16.6 ± 2.6
27.4 ± 4.3*
21.6 ± 2.7*
20.2 ± 1.6*
18.4 ± 2.6065
302211B16 melanoma

Lewis lung carcinoma

Dose(mg/kg)

MSD

ILS (%)

Saline32 X 1016 X 108 X 104 X 10

19.4 ± 1.9
NT22.2 ± 0.4*
21.0 ± 2.3
22.0 ± 1.40 		14		8		13		MSD

ILS (%)

Ehrlich carcinoma
MSD

16.6 ± 0.50 		18.5 ± 1.3
NT 		 37.0 ± 2.6*
20.6 ± 0.9*
24		
25.6 ± 7.2
19.2 ± 2.2
15		
18.3 ± 1.5
16.4 ± 3.
10		
18.8 ± 1.5

ILS (%)
01003801* P < 0.05
NT: not tested

3) Antimicrobial activity11)
Test organismMIC(µg/ml)

Pyricularia oryzae KF 180
Mucor racemosus KF 223 (IFO 4581)
Saccharomyces cerevisiae KF 26
Candida albicans KF 1
Penicillium herquei KF 227(IFO 4674)
Aspergillus niger KF 103 (ATCC 6275)

100>100>100>100100>1004) Inhibitory activity of ICAM-1 expression12)
Trienomycin A inhibited ICAM-1 expression. The inhibitory activity is closely related to theability to prevent translation. IC50 values against ICAM-1 expression incubated with TNF-α andwith IL-1α were 0.61 μM and 3.0 μM, respectively.
5) Cell growth inhibition13)
Trienomycin A inhibited cell growth of HeLa cells with IC50 values of 30 ng/ml. Trienomycin A
exhibited inhibitory activities against thapsigargin-induced XBP 1-luciferase activation with IC50values of 32 ng/ml. Trienomycin A is inhibitor of ER stress-induced XBP1 activation.
6) Inhibitory activity of NO production14)
Trienomycin A inhibited dose-dependently NO production in LPS-stimulated BV-2 cells with
EC50 value of 25.4 nM.

4. References
1.
I. Umezawa et al., J. Antibiot. 38, 699-705 (1985)
2.
S. Funayama et al., J. Antibiot. 38, 1107-1109 (1985)
3.
K. Komiyama et al., J. Antibiot. 38, 1677-1683 (1985)
4. [464] A. B. Smith, III, et al., Tetrahedron Lett. 32, 1627-1630 (1991)
5. [409] H. Nomoto et al., J. Antibiot. 42, 479-481 (1989)
6. [463] A. B. Smith, III et al., Tetrahedron Lett. 32, 841-842 (1991)
7. [447] A. B. Smith, III et al., J. Am. Chem. Soc. 112, 7425-7426 (1990)
8.
A. B. Smith, III et al., J. Am. Chem. Soc. 117, 10777-10778 (1995)
9.
A. B. Smith, III et al., J. Am. Chem. Soc. 118, 8316-8328 (1996)
10. [400] S. Funayama et al., J. Antibiot. 41, 1223-1230 (1988)
11. [378] K. Komiyama et al., J. Antibiot. 40, 1768-1772 (1987)
12.		
Y. Yamada et al., J. Antibiot. 64, 361-366 (2011)
13.		
E. Tashiro et al., J. Antibiot. 60, 547-553 (2007)
14.		
W.-G. Kim et al., J. Antibiot. 55, 204-207 (2002)