Cephalotaxus Alkaloids.

Cephalotaxus alkaloids represent a family of plant secondary metabolites known for 60 years. Significant activity against leukemia in mice was demonstrated for extracts of Cephalotaxus. Cephalotaxine (CET) (1), the major alkaloid of this series was isolated from Cephalotaxus drupacea species by Paudler in 1963. The subsequent discovery of promising antitumor activity among new Cephalotaxus derivatives reported by Chinese, Japanese, and American teams triggered extensive structure elucidation and biological studies in this family. The structural feature of this cephalotaxane family relies mainly on its tetracyclic alkaloid backbone, which comprises an azaspiranic 1-azaspiro[4.4]nonane unit (rings C and D) and a benzazepine ring system (rings A and B), which is linked by its C3 alcohol function to a chiral oxygenated side chain by a carboxylic function alpha to a tetrasubstituted carbon center. The botanical distribution of these alkaloids is limited to the Cephalotaxus genus (Cephalotaxaceae). The scope of biological activities of the Cephalotaxus alkaloids is mainly centered on the antileukemic activity of homoharringtonine (HHT) (2), which in particular demonstrated marked benefits in the treatment of orphan myeloid leukemia and was approved as soon as 2009 by European Medicine Agency and by US Food and Drug Administration in 2012. Its exact mechanism of action was partly elucidated and it was early recognized that HHT (2) inhibited protein synthesis at the level of the ribosome machinery. Interestingly, after a latency period of two decades, the topic of Cephalotaxus alkaloids reemerged as a prolific source of new natural structures. To date, more than 70 compounds have been identified and characterized. Synthetic studies also regained attention during the past two decades, and numerous methodologies were developed to access the first semisynthetic HHT (2) of high purity suitable for clinical studies, and then high grade enantiomerically pure CET (1), HHT (2), and analogs.

In silico studies, synthesis and binding evaluation of substituted 2-pyrrolidinones as peptidomimetics of RGD tripeptide sequence.

In silico optimisation, synthesis and binding evaluation of αvß3 integrin's affinity for precursors of a new RGD peptidomimetics family are presented. The 2-pyrrolidinone building block was obtained by condensation of l-lysine with dimethoxydihydrofuran followed by reduction. The ring was functionalized with a carboxylic acid and a guanidinium appendage. On the pyrrolidinone heterocycle, the effects on affinity of position, length and relative geometry of the two acid or basic functionalized side chains introduced on the pyrrolidinone ring have been previously evaluated by docking studies. Peptidomimetics have finally been evaluated by competition binding assays for αvß3 integrin's affinity using radio-ligands.

Optimized multimodal nanoplatforms for targeting α(v)ß3 integrins.

Magnetic Resonance Imaging (MRI) using contrast agents is a very powerful technique for diagnosis in clinical medicine and biomedical research. The synthesis of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles targeting αvß3 integrins and acting as new MRI contrast agents seems to be a promising way for cancer diagnosis. Indeed, it is well established that αvß3 integrin plays a key role in tumor angiogenesis acting like a receptor for the extracellular matrix proteins like vitronectin, fibronectin through the arginine-glycine-aspartic acid (RGD) sequence. Up-regulation of αvß3 has been found to be associated with a wide range of cancers, making it a broad-spectrum tumor-marker. In this study, USPIO nanocrystals were synthesized and surface passivated with caffeic acid. The large number of the carboxylic acid functions at the outer surface of the nanoplatforms was used for the covalent coupling of Rhodamine123, polyethylene glycol (PEG) and cyclic RGD. Soluble carbodiimide (EDC) and N-hydroxysuccinimide (NHS) were used to crosslink carboxylic acid with the amino group of the ligands. We examined the design of the nanoplatforms with each individual entity and then the combination of two and three of them. Several methods were used to characterize the nanoparticle surface functionalization and the magnetic properties of these contrast agents were studied using a 1.5 T clinical MRI scanner. The affinity towards integrins was evidenced by surface plasmon resonance and solid-phase receptor-binding assay.

Stereoselective synthesis of (-)-cephalotaxine and C-7 alkylated analogues.

A total asymmetric synthesis of (-)-cephalotaxine is reported. The chemistry of alpha,beta-unsaturated gamma-lactams was used to access the 1-azaspiro[4.4]nonane skeleton in enantiomerically pure form via a stereocontrolled semipinacolic rearrangement of an alpha-hydroxyiminium ion. This spiro compound was transformed into (-)-cephalotaxine without any racemization or epimerization by following the racemic synthesis reported by Kuehne. We thus performed a total synthesis of (-)-cephalotaxine in 98.7% ee with an overall yield of 9.8% over a 16 steps sequence. This synthetic process was adaptable to the access of some alkylated analogues.