1,2-Amino Alcohols and Their Heterocyclic Derivatives as Chiral Auxiliaries in Asymmetric Synthesis

Drug discovery from marine natural products has enjoyed a renaissance in the past few years. Ziconotide (Prialt; Elan Pharmaceuticals), a peptide originally discovered in a tropical cone snail, was the first marine-derived compound to be approved in the United States in December 2004 for the treatment of pain. Then, in October 2007, trabectedin (Yondelis; PharmaMar) became the first marine anticancer drug to be approved in the European Union. Here, we review the history of drug discovery from marine natural products, and by describing selected examples, we examine the factors that contribute to new discoveries and the difficulties associated with translating marine-derived compounds into clinical trials. Providing an outlook into the future, we also examine the advances that may further expand the promise of drugs from the sea.

Drug development from marine natural products

(First of Two Parts) COLLAGEN is the major macromolecule of most connective tissues, and it is widely believed that many human diseases, particularly chronic diseases, will be found to involve this protein either directly or indirectly. Since collagen biosynthesis was last reviewed in the Journal in 1972,1 much new information has been gained about the relatively complex pathway by which it is synthesized. We should like to consider this new information and some of its consequences in terms of the following questions: What is the structural information in the collagen molecule, and how does it determine the structure of the . . .

Biosynthesis of collagen and its disorders

Cyanobacterial secondary metabolites have attracted increasing scientific interest due to bioactivity of many compounds in various test systems. Among the known structures, oligopeptides are often found with many congeners sharing conserved substructures, while being highly variable in others. A major part of known oligopeptides are of non-ribosomal origin and can be grouped into classes with conserved structural properties. Thus, the overall structural diversity of cyanobacterial oligopeptides only seemingly suggests an equally high diversity of biosynthetic pathways and respective genes. For each class of peptides, some of which have been found in all major branches of the cyanobacterial evolutionary tree, homologous synthetases and genes can be inferred. This implies that non-ribosomal peptide synthetase genes are a very ancient part of the cyanobacterial genome and presumably have evolved by recombination and duplication events to reach the present structural diversity of cyanobacterial oligopeptides. In addition, peptide synthetases would appear to be an essential part of the cyanobacterial evolution and physiology. The present review presents an overview of the biosynthesis of cyanobacterial peptides and corresponding gene clusters, the structural diversity of structural types and structural variations within peptide classes, and implications for the evolution and plasticity of biosynthetic genes and the potential function of cyanobacterial peptides.

Cyanobacterial peptides – Nature's own combinatorial biosynthesis

The marine environment has proven to be a very rich source of extremely potent compounds that have demonstrated significant activities in antitumor, antiinflammatory, analgesia, immunomodulation, allergy, and anti-viral assays. Although the case can and has been made that the nucleosides such as Ara-A and Ara-C are derived from knowledge gained from investigations of bioactive marine nucleosides, no drug directly from marine sources (whether isolated or by total synthesis) has yet made it to the commercial sector in any disease. However, as shown in this review, there are now significant numbers of very interesting molecules that have come from marine sources, or have been synthesized as a result of knowledge gained from a prototypical compound, that are either in or approaching Phase II/III clinical trials in cancer, analgesia, allergy, and cognitive diseases. A substantial number of other potential agents are following in their wake in preclinical trials in these and in other diseases.

Marine Natural Products and Related Compounds in Clinical and Advanced Preclinical Trials

Antineoplastic cyclic peptides from the marine tunicate Lissoclinum patella

Gallium nitrate, administered intravenously to patients with advanced cancer, produced renal functional abnormalities consistently at a dose of 750 mg/m2. The toxicity at that dose could be modified by fluid loading and osmotic diuresis. Pharmacokinetic studies revealed a biphasic half-life, (T 1/2 alpha = 87 minutes and T 1/2 beta = 24.5 hours). Osmotic diuresis reduced the urinary concentration of gallium but did not affect serum levels or clearance.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%28197911%2944%3A5%3C1722%3A%3AAID-CNCR2820440528%3E3.0.CO%3B2-C

Clinical toxicologic and pharmacologic studies of gallium nitrate

Dolastatin-10 is a novel pentapeptide agentoriginally isolated from the marine molluskDolabella auricularia with amechanism of antitumor activity thatinvolves the inhibition of microtubuleassembly. We performed a Phase II trial ofDolastatin-10, 400 μg/m2, inpatients with advanced melanoma who hadreceived no prior chemotherapy. Dolastatin-10 pharmokinetics wereevaluated in a subset of patients followingcourses 1 and 2. Twelve patients weretreated with a median of 2 cycles ofDolastatin-10, and no patient experiencedan objective response. The only grade >2toxicities were grade 3 neutropeniauncomplicated by infection, occurring in 4patients following the first treatmentcycle. The total systemic clearance andvolume of distribution at steady-state were2.61 ± 1.9 L/h/m2 and 28.4 ± 13 L/m2,respectively. Due toprolonged terminal elimination,Dolastatin-10 plasma concentrations ofgreater than 1 nM were sustained for 24h in all patients studied. Dolastatin-10 is unlikely to havesubstantial activity in the treatment ofmelanoma.

Dolastatin-10 in metastatic melanoma: a phase II and pharmokinetic trial of the California Cancer Consortium.

Multiple daily injections of triamcinolone diacetate to newborn rats result in decreased body and skin weight gain, which is related to a specific decrease of collagen polypeptide synthesis. The effects of glucocorticoid administration on protein synthesis of the dermis was determined by measurement of the incorporation of labeled proline. The percentage decrease in collagen synthesis in triamcinolone-treated animals was greater than that of non-collagen protein synthesis at all doses examined, indicating a selective effect of glucocorticoids on collagen synthesis. This selective decrease of collagen synthesis was greatest after multiple injections at higher doses of the steroid. DNA synthesis was also suppressed after multiple injections of steroid. Steroid administration resulted in a decrease in prolyl hydroxylase activity (EC 1.14.11.2) in a dose- and time-dependent manner. Lysyl hydroxylase activity (EC 1.14.11.4) was decreased to the same extent as prolyl hydroxylase activity, while glucose 6-phosphate dehydrogenase activity (EC 1.1.1.49) was unchanged and tyrosine aminotransferase activity (EC 2.6.1.5) was slightly elevated. Collagenase digestion of nascent polypeptide chains released from dermal polysomes demonstrated a selective, dose-dependent decrease in collagen polypeptide synthesis. Furthermore, collagen nascent chain synthesis was decreased to the same extent as hydroxyproline formation, indicating that glucocorticoids do not cause the synthesis and subsequent accumulation of underhydroxylated collagen.

Glucocorticoids Selectively Decrease the Synthesis of Hydroxylated Collagen Peptides

Administration of gallium nitrate to rats resulted in the formation of renal precipitates which occluded tubular lumina. When analyzed with a combination of scanning electron microscopy and x-ray energy spectrometry, these precipitates were found to contain gallium complexed with calcium and phosphate. Injection of gallium nitrate also resulted in hypercalciuria, although serum calcium levels remained unaltered. Administration of an osmotic diuretic, isosorbide, prior to gallium treatment resulted in the formation of fewer renal precipitates and histopathologic changes than in the nondiuresed animals. Diuresis did not alter gallium serum pharmacokinetics, the 24 hour cumulative renal excretion of gallium or the extent of the drug-induced hypercalciuria. However, isosorbide pretreatment significantly reduced the urinary concentrations of both gallium and calcium. The data presented indicate that diuresis reduces the severity of gallium-induced renal lithiasis and subsequent renal accumulation of gallium by diluting the urinary concentration of gallium and calcium thereby lowering the incidence of interaction of these two elements within the kidney tubule.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%28197911%2944%3A5%3C1728%3A%3AAID-CNCR2820440529%3E3.0.CO%3B2-S

Robert A. Newman

Papers

Antineoplastic cyclic peptides from the marine tunicate Lissoclinum patella

Clinical toxicologic and pharmacologic studies of gallium nitrate

Dolastatin-10 in metastatic melanoma: a phase II and pharmokinetic trial of the California Cancer Consortium.

Glucocorticoids Selectively Decrease the Synthesis of Hydroxylated Collagen Peptides

Gallium nitrate (NSC-15200) induced toxicity in the rat: a pharmacologic, histopathologic and microanalytical investigation.