Intraluminal magnetisation of bowel by ferromagnetic particles for retraction and manipulation by magnetic probes.

Feasibility studies are needed to demonstrate that safe and effective manipulation of bowel during Minimal Access Surgery (MAS) can be obtained by use of magnetic force. This paper characterises two classes of magnetic particles: stainless steel microparticles (SS-µPs) and iron oxide nanoparticles (IO-nPs) in terms of their magnetisation, chemical composition, crystallinity, morphology and size distribution. Both magnetic particles were dispersed in a high viscosity biological liquid for intraluminal injection of bowel. Ex vivo porcine bowel segments were then retracted by permanent magnetic probes of 5.0 and 10mm diameter. Strong retraction forces reaching 6N maximum were obtained by magnetic fluid based on dispersion of SS-µPs. In contrast, the IO-nP-based magnetic liquid generated less attraction force, due to both lower magnetic and solution properties of the IO-nPs. The comparison of the two particles allowed the identification of the rules to engineer the next generation of particles. The results with SS-µPs provide proof on concept that intraluminal injection of magnetic fluid can generate sufficient force for efficient bowel retraction. Thereafter we shall carry out in vivo animal studies for efficacy and safety of both types of ferrofluids.

The chemical synthesis of discodermolide.

The marine sponge-derived polyketide discodermolide is a potent antimitotic agent that represents a promising natural product lead structure in the treatment of cancer. Discodermolide shares the same microtubule-stabilising mechanism of action as Taxol(®), inhibits the growth of solid tumours in animal models and shows synergy with Taxol. The pronounced cytotoxicity of discodermolide, which is maintained against cancer cell lines that display resistance to Taxol and other drugs, combined with its scarce availability from its natural source, has fuelled significant academic and industrial interest in devising a practical total synthesis as a means of ensuring a sustainable supply for drug development. This chapter surveys the various total syntheses of discodermolide that have been completed over the period 1993-2007, focusing on the strategies employed for introduction of the multiple stereocentres and achieving control over the alkene geometry, along with the various methods used for realising the pivotal fragment couplings to assemble progressively the full carbon skeleton. This dedicated synthetic effort has triumphed in removing the supply problem for discodermolide, providing sufficient material for extensive biological studies and enabling its early stage clinical development, as well as facilitating SAR studies for lead optimisation.

A practical synthesis of (+)-discodermolide and analogues: fragment union by complex aldol reactions.

A practical stereocontrolled synthesis of (+)-discodermolide (1) has been completed in 10.3% overall yield (23 steps longest linear sequence). The absolute stereochemistry of the C(1)-C(6) (7), C(9)-C(16) (8), and C(17)-C(24) (9) subunits was established via substrate-controlled, boron-mediated, aldol reactions of the chiral ethyl ketones 10, 11, and 12. Key fragment coupling reactions were a lithium-mediated, anti-selective, aldol reaction of aryl ester 8 (under Felkin-Anh induction from the aldehyde component 9), followed by in situ reduction to produce the 1,3-diol 40, and a (+)-diisopinocampheylboron chloride-mediated aldol reaction of methyl ketone 7 (overturning the inherent substrate induction from the aldehyde component 52) to give the (7S)-adduct 58. The flexibility of our overall strategy is illustrated by the synthesis of a number of diastereomers and structural analogues of discodermolide, which should serve as valuable probes for structure-activity studies.