The total synthesis of okadaic acid

In our recent review on the impact of natural products as a vehicle for discovery, especially for carbon-carbon bond or ring-forming events during particularly challenging steps of a synthesis, the reader can experience the knowledge, the commitment and effort needed to assemble these fascinating structures.

effort to the total synthesis of the natural product okadaic acid

Induction of manganese superoxide dismutase mRNA by okadaic acid and protein synthesis inhibitors.

synthesis of okadaic acid led ..

Welcome to Steve Ley’s research group webpages. Our laboratories, the Whiffen and Innovative Technology Centre are in the Department of Chemistry at the University of Cambridge. Here you’ll find out about our current research in flow chemistry and organic synthesis, as well as a look back at our historical achievements in natural product synthesis. We’re always keen to host academic and industry visitors and you are invited to get in touch.

an efficient and flexible total synthesis of okadaic acid was ..

N2 - Control of protein synthesis in insulin-responsive tissues has been well characterized, but relatively little is known about how this process is regulated in nervous tissues. The retina exhibits a relatively high protein synthesis rate, coinciding with high basal Akt and metabolic activities, with the majority of retinal ATP being derived from aerobic glycolysis. We examined the dependency of retinal protein synthesis on the Akt-mTOR signaling and glycolysis using ex vivo rat retinas. Akt inhibitors significantly reduced retinal protein synthesis but did not affect glycolytic lactate production. Surprisingly, the glycolytic inhibitor 2-deoxyglucose (2-DG) markedly inhibited Akt1 and Akt3 activities, as well as protein synthesis. The effects of 2-DG, and 2-fluorodeoxyglucose (2-FDG) on retinal protein synthesis correlated with inhibition of lactate production and diminished ATP content, with all these effects reversed by provision of D-mannose. 2-DG treatment was not associated with increased AMPK, eEF2, or eIF2α phosphorylation; instead, it caused rapid dephosphorylation of 4E-BP1. 2-DG reduced total mTOR activity by 25%, but surprisingly, it did not reduce mTORC1 activity, as indicated by unaltered raptor-associated mTOR autophosphorylation and ribosomal protein S6 phosphorylation. Dephosphorylation of 4E-BP1 was largely prevented by inhibition of PP1/PP2A phosphatases with okadaic acid and calyculin A, and inhibition of PPM1 phosphatases with cadmium. Thus, inhibition of retinal glycolysis diminished Akt and protein synthesis coinciding with accelerated dephosphorylation of 4E-BP1 independently of mTORC1. These results demonstrate a novel mechanism regulating protein synthesis in the retina involving an mTORC1-independent and phosphatase-dependent regulation of 4E-BP1.

In the second part of this thesis, the synthesis of the C1S-C27 domain of okadaic acid is accomplished.
Formal total synthesis of okadaic acid via regiocontrolled gold(I)-catalyzed spiroketalizations.

Ribonucleic acid synthesis of ..

Recently, the p38 mitogen-activated protein kinase (MAPK) pathway has been reported to be involved in tyrosinase degradation.) Thus, we determined whether okadaic acid induces the phosphorylation of p38 MAPK in Mel-Ab cells. Although p38 MAPK was phosphorylated in okadaic acid-treated cells, SB203580, a p38 MAPK inhibitor, did not abrogate the inhibition of melanin synthesis by okadaic acid, indicating that p38 MAPK may not be the primary signaling pathway involved in okadaic acid-induced hypopigmentation (data not shown).

synthesis of polyether natural products part ..

doi:10.1021/jo00170a070 - ACS Publications Home Page

The exquisite diversity, reactivity and biological function of these molecules constantly challenges the very frontiers of our science in terms of assembly and reactivity. The target-orientated approach imposes a discipline which is hard to match by other areas of chemistry. Natural product synthesis has a rich history of discovery and innovation which continues today; often it provides the basis to ask new questions and solve previously considered impossible processes, thereby leading to step-change advances and transformation of the subject.

Okadaic acid is a C 38 fatty acid derivative that is known to specifically inhibit the activity of protein phosphatase 2A (PP2A)

Rapamycin, >99% | LC Laboratories

(A) After 24 h of serum starvation, Mel-Ab cells were treated with 100 n okadaic acid for the indicated times. Whole cell lysates were then analyzed by Western blotting with antibodies against phospho-ERK, phospho-Akt, phospho-GSK3β, and β-catenin. Equal protein loading was confirmed by use of an actin antibody. Mel-Ab cells were incubated with 100 n okadaic acid for 24–72 h. Whole cell lysates were analyzed by Western blotting with antibodies against (B) MITF and tyrosinase, or (C) phospho-GSK3β and total GSK3β. Equal protein loading was confirmed by use of an actin antibody. (D) The mRNA levels of tyrosinase and GAPDH (as a loading control) were determined by RT-PCR assays as described in Materials and Methods. The resulting PCR products were analyzed by agarose gel electrophoresis. M, marker.