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Biomedical subjects

K C Nicolaou

Publications and source records attributed to K C Nicolaou.

At least 19 recordsLinked to original sources
PubMed2007

Effects of azaspiracid-1, a potent cytotoxic agent, on primary neuronal cultures. A structure-activity relationship study.

Azaspiracids (AZAs) are marine phycotoxins with an unknown mechanism of action, implicated in human intoxications. We investigated the effect of azaspiracid-1 (AZA-1) on the cytosolic calcium concentration ([Ca2+]c), intracellular pH (pHi), and neuron viability in neuronal cultures. AZA-1 increased [Ca2+]c and decreased neuronal viability. The effects of several fragments of the AZA-1 molecule (13 different chemical structures) were examined. The ent-ABCD-azaspiracid-1 (2) showed similar potency to AZA-1 (1) in increasing [Ca2+]c but higher cytotoxity than AZA-1. The chemical structures containing only the ABCD or the ABCDE ring domains (3-8) caused a [Ca2+]c increase but did not alter cell viability. The compounds containing only the FGHI ring domain of AZA-1 (9-14) did not modify the [Ca2+]c or the cell viability. Therefore, the effect of AZA-1 on [Ca2+]c depends on the presence of the ABCD or the ABCDE-ring structure, but the complete chemical structure is needed to produce neurotoxic effects.

Actins↗
PubMed2007

Total synthesis of abyssomicin C, atrop-abyssomicin C, and abyssomicin D: implications for natural origins of atrop-abyssomicin C.

In this article, the total syntheses of the antibiotic abyssomicin C (1) and its biologically inactive sibling abyssomicin D (3) are described. A number of unforseen roadblocks in our synthetic plan encouraged innovation, which culminated in the discovery of a new Lewis acid-templated Diels-Alder reaction. En route to abyssomicin C, we prepared and characterized its stable conformational isomer atrop-abyssomicin C (57), which in the presence of a strong acid underwent an unusual interconversion with the targeted natural product. Close inspection of the X-ray crystallographic structures of these compounds led to hypotheses on the mechanism of their interconversion. Attempted reduction of both atropisomers revealed that atrop-abyssomicin C afforded abyssomicin D much more readily, suggesting that this previously unknown atropisomer may be synthesized by the host organism and serves as a direct precursor of abyssomicin D. Finally, to gain insight into the mechanism of antiobiotic activity, several synthetic intermediates and designed analogues were evaluated for biological activity.

Anti-Bacterial Agents↗
PubMed2006

Cascade reactions in total synthesis.

The design and implementation of cascade reactions is a challenging facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to synthetic strategies. The application of cascade reactions to natural products synthesis represents a particularly demanding task, but the results can be both stunning and instructive. This Review highlights selected examples of cascade reactions in total synthesis, with particular emphasis on recent applications therein. The examples discussed herein illustrate the power of these processes in the construction of complex molecules and underscore their future potential in chemical synthesis.

Biological Products↗
PubMed2006

Synergistic effects of peloruside A and laulimalide with taxoid site drugs, but not with each other, on tubulin assembly.

Previous studies on the drug content of pelleted tubulin polymers suggest that peloruside A binds in the laulimalide site, which is distinct from the taxoid site. In a tubulin assembly system containing microtubule-associated proteins and GTP, however, peloruside A was significantly less active than laulimalide, inducing assembly in a manner that was most similar to sarcodictyins A and B. Because peloruside A thus far seems to be the only compound that mimics the action of laulimalide, we examined combinations of microtubule-stabilizing agents for synergistic effects on tubulin assembly. We found that peloruside A and laulimalide showed no synergism but that both compounds could act synergistically with a number of taxoid site agents [paclitaxel, epothilones A/B, discodermolide, dictyostatin, eleutherobin, the steroid derivative 17beta-acetoxy-2-ethoxy-6-oxo-B-homo-estra-1,3,5(10)-trien-3-ol, and cyclostreptin]. None of the taxoid site compounds showed any synergism with each other. From an initial study with peloruside A and cyclostreptin, we conclude that the synergism phenomenon derives, at least in part, from an apparent lowering of the tubulin critical concentration with drug combinations compared with single drugs. The apparent binding of peloruside A in the laulimalide site led us to attempt construction of a pharmacophore model based on superposition of an energy-minimized structure of peloruside A on the crystal structure of laulimalide. Although the different sizes of the macrocycles limited our ability to superimpose the two molecules, atom correspondences that were observed were consistent with the difficulty so far experienced in creation of fully active analogs of laulimalide.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed2006

Azaspiracids modulate intracellular pH levels in human lymphocytes.

The azaspiracids (AZAs) are a group of marine toxins implicated in several intoxications whose mechanism of action is unknown. These phycotoxins include the five compounds shown in : AZA-1 (1), AZA-2 (2), AZA-3 (3), AZA-4 (4), and AZA-5 (5). The aim of this work was to study the effects of the five naturally occurring azaspiracids (AZA-1 to -5, Fig. 1) and four synthetic analogues (6-9, Fig. 2) on intracellular pH, and the influence of Ca2+ upon this effect. The AZAs (1-5) were found to modulate cytosolic Ca2+ levels in human lymphocytes, while some of them, but not all, had effects on the intracellular pH. AZA-1 (1) and AZA-2 (2) did not modify intracellular pH in a Ca2+-containing or a Ca2+-free medium. AZA-3 (3) increased intracellular pH by 0.16 units in the presence of extracellular Ca2+, an effect that was blocked when a 1 mM solution of Ni2+ was added. In a Ca2+-free medium, the increase in pH induced by AZA-3 (3) was reduced to 0.08 pH units. AZA-4 (4) inhibited the basal pH increase even in the presence of a 1 mM solution of Ni2+. In a Ca2+-free medium, the inhibition caused by AZA-4 (4) was small, but when Ca2+ was added back to the medium, the pH basal increase was again significantly inhibited. The alkalinization was also inhibited when AZA-4 (4) was added simultaneously, 10 min before or 10 min after thapsigargin (Tg), and also when the Ca2+-influx induced by Tg was inhibited by Ni2+. AZA-5 (5), on the other hand, did not modulate the intracellular pH profile in either a Ca2+-containing or a Ca2+-free medium. Finally, we investigated four synthetic analogues (6-9, Fig. 2) whose structures were based on the four originally proposed structures of azaspiracid-1, with an opened E-ring. Compound 6 induced a small cytosolic Ca2+ increase, but did not modify intracellular pH in saline solution. In a Ca2+-free medium, compound 6 blocked the pH fall when Ca2+ was added back to the medium. Compound 7 also did not modify intracellular pH in saline solutions, however it significantly blocked basal pH increases in a Ca2+-free medium. Compound 8 did not alter intracellular pH, however compound 9 induced a small acidification when Ca2+ was present in the extracellular medium. These results point to a structure-activity relationship in AZAs pH effect that affects the modulation and the coupling of intracellular pH and Ca2+.

Calcium↗
PubMed2006

Synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures. Revised strategy and final stages.

A general and highly convergent synthetic route to the macrocyclic core structures of the antitumour agents amphidinolide N (1) and caribenolide I (2) has been developed, and the total synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures is described. Central to the revised strategy was the use of a Horner-Wadsworth-Emmons olefination between beta-ketophosphonate 51 and aldehyde 14 to construct the C1-C13 sector common to both 1 and 2. Stereoselective alkylation of hydrazone 11 with iodide 65 and then with bromide 56 allowed for the rapid assembly of the complete caribenolide I carbon skeleton. Key steps in the completion of the synthesis of des-epoxy-caribenolide I structure 78 included hydrolysis of a sensitive methyl ester using Me(3)SnOH, followed by regioselective macrolactonisation of the resulting diol seco-acid and global deprotection. Coupling of hydrazone 11, bromide 56 and iodide 64 was followed by an analogous sequence of late-stage manoeuvres to arrive at the fully deprotected des-epoxy-amphidinolide N framework, obtained as a mixture of hemiacetal and bicyclic acetal 84. Regio- and diastereo-selective epoxidation of the C6 methylene group in bicyclic acetal 84 provided access to iso-epoxy-amphidinolide N stereoisomer 89.

Alkynes↗
PubMed2006

Synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures. Initial forays.

Two strategies for the projected total synthesis of the phenomenally potent antitumour macrolides amphidinolide N (1) and caribenolide I (2) are described. The title compounds are introduced as challenging and unique targets for chemical synthesis, and their retrosynthetic analysis is presented. The synthesis of the four defined key building blocks (10, 39, 67 and 72), required for the construction of amphidinolide N (1), in their enantiomerically pure forms, is described, followed by the coupling of 10, 39 and 72 through hydrazone alkylation processes to generate the complete C6-C29 carbon framework of the target compound (1). Fusion of the remaining C1-C5 sector (72) onto the molecule by metathesis-based methods was unsuccessful, resulting in the adoption of a second-generation strategy which called for the employment of one of the array of palladium-catalysed cross-coupling reactions to generate the C5-C6 carbon-carbon bond. Vinyl bromide 125, representing the C6-C29 skeleton of caribenolide I (2), was prepared through the sequential alkylation of hydrazone 10 with bromide 116 and iodide 55, but failed to engage in the appropriate cross-coupling reaction with a variety of C1-C4 partners. Despite these setbacks, the information gleaned from these endeavours was to prove invaluable in laying the foundation for the eventual successful approach to the macrocyclic structures of amphidinolide N (1) and caribenolide I (2).

Antineoplastic Agents↗
PubMed2006

Total synthesis and biological evaluation of halipeptins A and D and analogues.

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).

Anti-Infective Agents↗
PubMed2006

Total synthesis and structural elucidation of azaspiracid-1. Final assignment and total synthesis of the correct structure of azaspiracid-1.

The molecular structure of azaspiracid-1, a neurotoxin isolated from mussels, has been elucidated by total synthesis which also enriched its supplies. The degradatively derived fragments of this marine biotoxin, compounds 5 (EFGHI), 6 (FGHI), and 40 (ABCD), were matched with synthetic materials, thus confirming their structural identities. Based on this detective work, a new structure of azaspiracid-1 (i.e., 1) was proposed and constructed by total synthesis. The final strategy for the total synthesis of azaspiracid-1 featured a dithiane anion (C(21)-C(27) fragment) reacting with a pentafluorophenol ester (C(1)-C(20) fragment) followed by a Stille-type union of an advanced allylic acetate substrate (C(1)-C(27) fragment) with a vinyl stannane as the main coupling processes to assemble the carbon skeleton of the molecule. In addition to the total synthesis of azaspiracid-1 (1), the syntheses of its C(1)-C(20) epimer (2) and of several truncated analogues for biological investigations are described.

Animals↗
PubMed2006

Total synthesis and structural elucidation of azaspiracid-1. Construction of key building blocks for originally proposed structure.

Syntheses of the three key building blocks (65, 98, and 100) required for the total synthesis of the proposed structure of azaspiracid-1 (1a) are described. Key steps include a TMSOTf-induced ring-closing cascade to form the ABC rings of tetracycle 65, a neodymium-catalyzed internal aminal formation for the construction of intermediate 98, and a Nozaki-Hiyama-Kishi coupling to assemble the required carbon chain of fragment 100. The synthesized fragments, obtained stereoselectively in both their enantiomeric forms, were expected to allow for the construction of all four stereoisomers proposed as possible structures of azaspiracid-1 (1a-d), thus allowing the determination of both the relative and absolute stereochemistry of the natural product.

Crystallography, X-Ray↗