Total Synthesis and Biological Evaluation of Halipeptins A and D and Analogues

Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
Journal of the American Chemical Society (Impact Factor: 12.11). 05/2006; 128(13):4460-70. DOI: 10.1021/ja060064v
Source: PubMed


The marine-derived halipeptins A (1a) and D (1d) and their analogues 3a, 3d and 4a, 4d were synthesized starting from building blocks 10, 13, 14a or 14d, 15, and 16. The first strategy for assembling the building blocks, involving a macrolactamization reaction to form the 16-membered ring hydroxy thioamide 52d as a precursor, furnished the epi-isoleucine analogue (4d) of halipeptin D, whereas a second approach involving thiazoline formation prior to macrolactamization led to a mixture of halipeptins A (1a) and D (1d) and their analogues 3a, 3d (epimers at the indicated site) and 4a, 4d (epimers at the indicated site). The same route starting with D-Ala resulted in the exclusive formation of the epimeric halipeptin D analogue 3d. The synthesized halipeptins, together with the previously constructed oxazoline analogues 5d and 6d, were subjected to biological evaluation revealing anti-inflammatory properties for 1a, 1d, and 6d while being noncytotoxic against human colon cancer cells (HCT-116).

Download full-text


Available from: Manuela Rodriquez,
  • Source
    • "Particular attention has been focused on halipeptin A, because of its potent biological activities. Halipeptin A is a cyclic depsipeptide, whose total synthesis has been successfully carried out [100], together with recent syntheses of halipeptin D and its analogues, in order to take advantage of their biological properties [101]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammation is a hot topic in medical research, because it plays a key role in inflammatory diseases: rheumatoid arthritis (RA) and other forms of arthritis, diabetes, heart diseases, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, allergies, asthma, even cancer and many others. Over the past few decades, it was realized that the process of inflammation is virtually the same in different disorders, and a better understanding of inflammation may lead to better treatments for numerous diseases. Inflammation is the activation of the immune system in response to infection, irritation, or injury, with an influx of white blood cells, redness, heat, swelling, pain, and dysfunction of the organs involved. Although the pathophysiological basis of these conditions is not yet fully understood, reactive oxygen species (ROS) have often been implicated in their pathogenesis. In fact, in inflammatory diseases the antioxidant defense system is compromised, as evidenced by increased markers of oxidative stress, and decreased levels of protective antioxidant enzymes in patients with rheumatoid arthritis (RA). An enriched diet containing antioxidants, such as vitamin E, vitamin C, β-carotene and phenolic substances, has been suggested to improve symptoms by reducing disease-related oxidative stress. In this respect, the marine world represents a largely untapped reserve of bioactive ingredients, and considerable potential exists for exploitation of these bioactives as functional food ingredients. Substances such as n-3 oils, carotenoids, vitamins, minerals and peptides provide a myriad of health benefits, including reduction of cardiovascular diseases, anticarcinogenic and anti-inflammatory activities. New marine bioactives are recently gaining attention, since they could be helpful in combating chronic inflammatory degenerative conditions. The aim of this review is to examine the published studies concerning the potential pharmacological properties and application of many marine bioactives against inflammatory diseases.
    Marine Drugs 04/2012; 10(4):812-33. DOI:10.3390/md10040812 · 2.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The majority of the anti-inflammatory drugs routinely used nowadays are COX (cyclo-oxygenase) inhibitors. The important role of this enzyme, once known as prostaglandin synthase, in inflammation came a consequence of the discovery by the Nobel prize winner John Vane with his path-breaking discovery that aspirin and similar drugs exert their action by blocking the biosynthesis of the prostaglandin group of lipid mediators. (John R. Vane, Nobel Lecture, December 8, 1982 and references cited therein) In the last five years it has become clear that there are two such enzymes involved. One of the "cyclo-oxygenases", called COX1 is responsible for making prostaglandins, which among other things, protect the stomach and kidney from damage. It is now clear that inhibition of COX1 accounts for the unwanted side effects of aspirin-like drugs such as gastric irritation and renal damage. The other enzyme, COX2, is induced by inflammatory stimuli and it is prostaglandins made by this enzyme that contribute to the inflammation in diseases such as rheumatoid arthritis. However, concerning inflammation-related targets, one should not limit the interest to COX and PLA2 enzymes. In recent years, it has steadily become more clear, that modulation in the expression of genes underlies most cellular responses, and inflammation is certainly not an exception in this sense. It does not come as surprise that molecules showing ability to interfere with factors involved in the modulation of genes expression, such as NF-kB, have also to be considered potential anti-inflammatory agents. Also in this respect, marine natural products (MNP) have brought a collection of novel molecular entities displaying ability to target COX1/COX2, NF-kappaB or acting through molecular mechanisms yet-to-be-discovered. Following, the marine natural products accounted for within this review will be grouped on the basis of their bio-molecular targets. Chemical synthesis of particular relevant molecules will be also discussed, especially in those cases where the natural products can be considered as lead compounds for the development of simplified derivatives or analogues of potential pharmaceutical interest.
    Current Medicinal Chemistry 02/2006; 13(16):1947-69. DOI:10.2174/092986706777585095 · 3.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
    ChemInform 09/2006; 2006(18):2996-3002. DOI:10.1055/s-2006-950198
Show more