A Novel Phospha Sugar Analogue: Synthesis And Evaluation Of 2,3-Dibromo-3-Methyl-1-Phenylphospholane 1-Oxide As A New Class Of Potential Anti-Proliferative Materials For Leukemia Cells

Abstract

A novel dideoxydibromophospha sugar analogue, 2,3-dibromo-3-methyl-l-phenylphospholane 1-oxide (1), was prepared from l-phenyl-3-methyl-2-phospholene 1-oxide (2) and evaluated by MTT in vitro methods for leukemia cells. The evaluation of dibromide 1 (mixture of diastereomers) as well as the separated diastereomer of dibromides la to Id from the diastereomer mixtures revealed clearly that the synthesized phospha sugar analogues have competent potentials and excellent anti-tumor activities for the human leukemia cells of K562 and U937 in selective and specific manner. The cell cycle analyses by flow cytometry for K562 and U937 cells clearly demonstrated that the mechanism of the anti-proliferative effect on the human tumor cells is apoptosis induced by the phospha sugar. Introduction Well known typical pseudo sugars are carba-, aza-, and /Aia-sugars, 1 " 3 with a carbon, nitrogen, and sulphur atom, respectively, instead of the oxygen atom in the hemiacetal ring of the normal sugars. These pseudo sugars are known to exist in nature and are also prepared by synthetic sugar chemistry. Pseudo sugars exert important biological activities, therefore, many studies on the isolation, synthesis, characterization, etc., are actively performed. On the other hand, phospha sugars, one new category of the pseudo sugars which have a phosphorus atom in the hemiacetal ring of sugars, are not yet found in nature and the synthesis of them are rather difficult compared with the typical pseudo sugars. 4 " 7 We have been searching biologically active phospha sugars and/or phosphorus heterocycles, and we have first found new anti-tumor phospha sugar derivatives by using 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl-2//-tetrazolium bromide (MTT) in vitro evaluation methods for some of these phospha sugars or phosphorus heterocycles against leukemia cells. 8 In this paper we will deal with the research on the synthesis, separation, and in vitro evaluation for 2,3-dibromo-3-methyl-l-phenylphospholane 1-oxide (1), one of dibromodideoxyphospha sugars, against human 273 Brought to you by | Purdue University Libraries Authenticated Download Date | 6/7/15 3:12 PM