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Gallinamide A

Gallinamide A
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
  • O=C1O[C@@]3(C)[C@H](C(=O)N[C@@]13[C@@H](O)[C@@H]2/C=C\CCC2)CCCl
Properties
C31H52N4O7
Molar mass 592.778 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Gallinamide A is potent and selective inhibitor of the human cysteine protease Cathepsin L1 that was first used as a moderate antimalarial agent. Gallinamide A is produced by marine cyanobacteria from Schizothrix species and Symploca sp.[1] which have also shown to have possible anticancer agent, infectious diseases like leishmaniasis, trypanosomiasis and possible uses in Alzheimer's disease, among others.[2]

History

Gallinamide A was first isolated from a Panamanian collection of marine cyanobacteria in 2009 (Schizothrix species) for activity against the malaria causing parasite Plasmodium falciparum.[3] Later, was subsequently and independently isolated by Taori and co-workers from a Floridian Cyanobacteria collection in Key Largo from Symploca sp. and given the name symplostatin 4.[4] Gallinamide A, among other cyanobacteria metabolites such as viridamide A & B, dragonamide E, and almiramide E; are lipodepsipeptides that proved to show anti-infective activities.[3] Gallinamide A was originally isolated with a modest antimalarial activity, which was then proven to be a potent inhibitor of cysteine protease cathepsin L with a IC50 5.0 ug/mL,[2] nonetheless, human cathepsin L is involved in many diseases, gallinamide A was tested in HeLa cervical cancer cells with a IC50 12 mM and in HT-29 colon adenocarcinoma cells with an IC50 of mM.

Mechanism of action

Gallinamide A is a potent and selective irreversible inhibitor of human Cathepsin L1, with a high selectivity towards cysteine cathepsin protease family.[1]

Total synthesis

The first stereoselective synthesis was reported by Conroy and co-workers.[3]

Clinical study

Gallinamide A is a potent inhibitor of cathepsin L with an IC50 value of 17.6 pM. Also, was tested for its antimalarial activity against the W2 chloroquine-resistant strain of the malaria parasite. This compound showed moderate in vitro activity against Plasmodium falciparum (IC50 = 8.4 μM), cytotoxicity to mammalian Vero cells (TC50 = 10.4 μM) and activity against Leishmania donovani of (IC50 = 9.3 μM), but was inactive up to the highest tested concentrations against Trypanasoma cruzi (16.9 μM). No in vivo or human testing has been perform since it is only for research development.[4]

References

  1. ^ a b Joshawna K Nunnery, Emily Mevers, William H Gerwick, Biologically active secondary metabolites from marine cyanobacteria, Current Opinion in Biotechnology, Volume 21, Issue 6, 2010, Pages 787-793, ISSN 0958-1669,
  2. ^ a b Boudreau, Paul D.; Miller, Bailey W.; McCall, Laura-Isobel; Almaliti, Jehad; Reher, Raphael; Hirata, Ken; Le, Thu; Siqueira-Neto, Jair L.; Hook, Vivian; Gerwick, William H. (24 October 2019). "Design of Gallinamide A Analogs as Potent Inhibitors of the Cysteine Proteases Human Cathepsin L and Trypanosoma cruzi Cruzain". Journal of Medicinal Chemistry. 62 (20): 9026–9044. doi:10.1021/acs.jmedchem.9b00294. PMC 7240701. PMID 31539239.
  3. ^ a b c Conroy, Trent; Guo, Jin T.; Elias, Nabiha; Cergol, Katie M.; Gut, Jiri; Legac, Jennifer; Khatoon, Lubna; Liu, Yang; McGowan, Sheena; Rosenthal, Philip J.; Hunt, Nicholas H.; Payne, Richard J. (26 December 2014). "Synthesis of Gallinamide A Analogues as Potent Falcipain Inhibitors and Antimalarials". Journal of Medicinal Chemistry. 57 (24): 10557–10563. doi:10.1021/jm501439w. hdl:2123/22261. PMID 25412465.
  4. ^ a b Miller, Bailey; Friedman, Aaron J.; Choi, Hyukjae; Hogan, James; McCammon, J. Andrew; Hook, Vivian; Gerwick, William H. (24 January 2014). "The Marine Cyanobacterial Metabolite Gallinamide A Is a Potent and Selective Inhibitor of Human Cathepsin L". Journal of Natural Products. 77 (1): 92–99. Bibcode:2014JNAtP..77...92M. doi:10.1021/np400727r. PMC 3932306. PMID 24364476.

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