Oxaphosphinanes: New Therapeutic Perspectives for Glioblastoma

Abstract

This paper reports the design and the synthesis of a new family of compounds, the phostines, belonging to the [1,2]oxaphosphinane family. Twenty-six compounds have been screened for their antiproliferative activity against a large panel of NCI cancer cell lines. Because of its easy synthesis and low EC(50) value (500 nM against the C6 rat glioma cell line), compound 3.1a was selected for further biological study. Moreover, the specific biological effect of 3.1a on the glioblastoma phylogenetic cluster from the NCI is dependent on its stereochemistry. Within that cluster, 3.1a has a higher antiproliferative activity than Temozolomide and is more potent than paclitaxel for the SF295 and SNB75 cell lines. In constrast with paclitaxel and vincristine, 3.1a is devoid of astrocyte toxicity. The original activity spectrum of 3.1a on the NCI cancer cell line panel allows the development of this family for use in association with existing drugs, opening new therapeutic perspectives.

Synthesis and Biological Applications of Phosphinates and Derivatives

“…The best treatment, which consists of surgical resection followed by chemotherapy with Temozolomide (TMZ) and radiotherapy, gives a median survival of 15 months as compared to 55 days with exeresis alone. To develop a new antiglioma therapy, Bakalara et al presented, in 2012, a new family of compounds, phostines, targeting CNS cancers without affecting normal astrocytes [126,127]. Phostines, which present a 1,2-oxaphosphinane heterocyclic core, were designed as a combination of glycopyranosides and C-arylglycosides (Fig.…”

Stereoselective Synthesis of α-Amino-C-phosphinic Acids and Derivatives

“…Additionally, the reaction of tris(benzyloxy)-D-arabinofuranose 113 with allylamine or benzylamine in the presence of MgSO4 in EtOH at reflux, provided the cyclic hemiaminal ethers 117a,b in 70% yield, which by nucleophilic addition of ethyl phenylphosphinate and cyclization in the presence of catalytic amounts of potassium tert-butoxide, afforded the 3-alkylamino-1,2-oxaphosphinanes 118a,b in 12% and 7% yield, respectively (Scheme 51) [98]. For example, the reaction of tris(benzyloxy)-D-arabinofuranose 113 with ethyl phenylphosphinate in the presence of catalytic amounts of potassium tert-butoxide followed by preparative reverse phase HPLC separation, led to the cyclic α-amino-C-phosphinate (2S,3R,4S,5S,6R)-114 in 17% yield.…”

“…The reaction of (2S,3R,4S,5S,6R)-114 with triflic anhydride in the presence of pyridine in CH2Cl2 at 0 °C, produced the triflate, which without additional purification it was reacted with trimethylsilylazide in the presence of TBAF in THF at 65 °C, obtaining the azido derivative (2S,3S,4S,5S,6R)-115 in 28% yield. Finally, reduction of azide group in the compound 115 with Ph3P/THF/H2O, furnished the glucose like oxaphosphinane (2S,3S,4S,5S,6R)-116 in 42% yield, which was tested for their antiproliferative activity in the search for new therapeutic agents against glioblastoma (Scheme 50) [98].…”

“…Additionally, the reaction of tris(benzyloxy)-D-arabinofuranose 113 with allylamine or benzylamine in the presence of MgSO4 in EtOH at reflux, provided the cyclic hemiaminal ethers 117a,b in 70% yield, which by nucleophilic addition of ethyl phenylphosphinate and cyclization in the presence of catalytic amounts of potassium tert-butoxide, afforded the 3-alkylamino-1,2-oxaphosphinanes 118a,b in 12% and 7% yield, respectively (Scheme 51) [98]. Additionally, the reaction of tris(benzyloxy)-D-arabinofuranose 113 with allylamine or benzylamine in the presence of MgSO 4 in EtOH at reflux, provided the cyclic hemiaminal ethers 117a,b in 70% yield, which by nucleophilic addition of ethyl phenylphosphinate and cyclization in the presence of catalytic amounts of potassium tert-butoxide, afforded the 3-alkylamino-1,2-oxaphosphinanes 118a,b in 12% and 7% yield, respectively (Scheme 51) [98].…”

“…Additionally, the reaction of tris(benzyloxy)-D-arabinofuranose 113 with allylamine or benzylamine in the presence of MgSO 4 in EtOH at reflux, provided the cyclic hemiaminal ethers 117a,b in 70% yield, which by nucleophilic addition of ethyl phenylphosphinate and cyclization in the presence of catalytic amounts of potassium tert-butoxide, afforded the 3-alkylamino-1,2-oxaphosphinanes 118a,b in 12% and 7% yield, respectively (Scheme 51) [98].…”