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. 2018 Oct 27;16(11):413.
doi: 10.3390/md16110413.

Synthesis and Evaluation of Spumigin Analogues Library with Thrombin Inhibitory Activity

Aleš Žula  1 , Izabela Będziak  2   3 , Danijel Kikelj  4 , Janez Ilaš  5
Affiliations

Synthesis and Evaluation of Spumigin Analogues Library with Thrombin Inhibitory Activity

Aleš Žula et al. Mar Drugs. .

Abstract

Spumigins are marine natural products derived from cyanobacteria Nodularia spumigena, which mimics the structure of the d-Phe-Pro-Arg sequence and is crucial for binding to the active site of serine proteases thrombin and factor Xa. Biological evaluation of spumigins showed that spumigins with a (2S,4S)-4-methylproline central core represent potential lead compounds for the development of a new structural type of direct thrombin inhibitors. Herein, we represent synthesis and thrombin inhibitory activity of a focused library of spumigins analogues with indoline ring or l-proline as a central core. Novel compounds show additional insight into the structure and biological effects of spumigins. The most active analogue was found to be a derivative containing l-proline central core with low micromolar thrombin inhibitory activity.

Keywords: marine products; natural peptides; peptidomimetics; thrombin inhibition.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of isolated spumigins.
Figure 2
Figure 2
Different types of designed spumigin A analogues.
Scheme 1
Scheme 1
Reagents and conditions of the synthesis of series A compounds: (a) 1H-imidazole-1-sulfonyl azide hydrochloride, K2CO3, CuSO4·5H2O, rt, 17 h; (b) ClCOCOCl, DCM, DMF, reflux, 2 h; (c) SOCl2, MeOH, reflux, 12 h; (d) CsCO3, CH3CN, 0 °C, 45 min; (e) LiOH, THF, rt, 2 h; (f) coupling reaction type A: AA derivative, Et3N, EDC, HOBt, DMF, rt, 12h; (g) coupling reaction type B: AA derivative, NMM, TBTU, DMF, rt, 13 h; (h) Pd/C, H2, EtOH, 8 h; (i) coupling reaction type C: d-Pla or (±)-Hpla, NMM, TBTU, DMF, rt, 16 h; (j) Pd(OH)2/C, H2, EtOH, HCOOH, 35 °C, 12 h; (k) pig liver esterase (148 U/mg protein), buffer (pH 7)/DMSO (10:1), 24 h, rt; * Absolute configuration of compounds was not experimentally determined; assigned configuration on indoline chiral centre is based on calculations of biological activity and measured optical rotation. rt—room temperature.
Scheme 2
Scheme 2
Reagents and conditions of the synthesis of series B compounds: (a) SOCl2, MeOH, reflux, 12 h; (b) EDC, HOBt, NMM,12 h, rt; (c) LiOH, THF, 2 h; (d) EDC, HOBt, NMM, l-Arg(NO2) methyl ester hydrochloride, 12 h; (e) HCl/MeOH, 8 h; (f) d-Pla or (±)-Hpla, TBTU, NMM, 6 h; (g) Pd(OH)2/C, H2, HCOOH, EtOH, 10 h.
Scheme 3
Scheme 3
Reagents and conditions of the synthesis of series A compounds: (a) 1H-imidazole-1-sulfonyl azide hydrochloride, K2CO3, CuSO4·5H2O, rt, 17 h; (b) (i) ClCOCOCl, DCM, DMF, reflux, 2 h; (ii) CsCO3, CH3CN, 0 °C, 45 min; (c) LiOH, THF, rt, 1 h; (d) l-Arg(NO2)-OMe, Et3N, EDC, HOBt, DMF, rt, 12 h; (e) Pd/C, H2, EtOH, 7 h; (f) d-Pla, NMM, TBTU, DMF, rt, 16 h; (j) Pd(OH)2/C, H2, EtOH, HCOOH, 35 °C, 12 h; * Absolute configuration of the compounds was not experimentally determined, assigned configuration on indoline chiral centre is based on calculations of biological activity and measured optical rotation.
Figure 3
Figure 3
Summary of SAR results.
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References

    1. Burja A.M., Banaigs B., Grant Burgess J. Marine cyanobacteria—A prolific source of natural products. Tetrahedron. 2001;57:9347–9377. doi: 10.1016/S0040-4020(01)00931-0. - DOI
    1. Mazur-Marzec H., Bertos-Fortis M., Toruńska-Sitarz A., Fidor A., Legrand C. Chemical and Genetic Diversity of Nodularia spumigena from the Baltic Sea. Mar. Drugs. 2016;14:209. doi: 10.3390/md14110209. - DOI - PMC - PubMed
    1. Liu L., Budnjo A., Jokela J., Haug B.E., Fewer D.P., Wahlsten M., Rouhiainen L., Permi P., Fossen T., Sivonen K. Pseudoaeruginosins, nonribosomal peptides in Nodularia spumigena. ACS Chem. Biol. 2015;10:725–733. doi: 10.1021/cb5004306. - DOI - PubMed
    1. Fujii K., Sivonen K., Adachi K., Noguchi K., Sano H., Hirayama K., Suzuki M., Harada K.-I. Comparative study of toxic and non-toxic cyanobacteria products: Novel peptides from toxic Nodularia spumigena AV1. Tetrahedron Lett. 1997;38:5525–5528. doi: 10.1016/S0040-4039(97)01192-1. - DOI
    1. Anas A.R., Kisugi T., Umezawa T., Matsuda F., Campitelli M.R., Quinn R.J., Okino T. Thrombin inhibitors from the freshwater cyanobacterium Anabaena compacta. J. Nat. Prod. 2012;75:1546–1552. doi: 10.1021/np300282a. - DOI - PubMed

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