الفهرس 
Synthetic Methods for Phosphorus Compounds Containing chromone RingOnly 14 pages are availabe for public view
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Abstract
Part I
Reaction of 2-hydroxy-N`-[(4-oxo-4H-chromen-3-yl)methylidene] benzohydrazide with some phosphorus reagents: synthesis and evaluation of anticancer activities of some novel α-hydrazinophosphonic acid, 1,4,5,2-oxadiazaphosphinines and 1,3,2-benzoxazaphosphinines bearing a chromone ring.
In the present work, we disclosed a methodology to synthesize six-membered phosphorus heterocycles with expected biological activities. The method depends on cyclization of 2-hydroxy-N`-[(4-oxo-4H-chromen-3-yl)methylidene]benzohydrazide (2) with different kind of phosphorus reagents such as phosphorus di-esters, phosphorus sulfides and phosphorus halides. The synthesized compounds were examined for their anticancer properties against human breast MCF-7, liver HepG2, colon HCT116 and prostate PC3 cancer cell lines that may act through angiogenesis inhibition. Treatment of 3-formylchromone (1) with salicylic acid hydrazide in absolute ethanol gave 2-hydroxy-N`-[(4-oxo-4H-chromen-3-yl)methylidene]benzohydrazide (2) in good yield (Scheme 1).
Scheme 1
Compound 2 could be used as a synthone to construct phosphorus heterocyclic systems containing the chromone nucleus. Thus, reaction of hydrazone 2 with phosphonic acid in dry dioxane containing 4-toluenesulfonic acid as a catalyst under Pudovik reaction conditions gave the corresponding α-hydrazinophosphonic acid 3 in moderate yield (Scheme 2). When hydrazone 2 was allowed to react with diethyl phosphite and tris(2-chloroethyl)phosphite in the presence of trifluoroboron etherate as a catalyst at 80−90 °C under Pudovik reaction conditions, affording the corresponding 1,4,5,2-oxadiazaphosphininyl chromones 4 and 5, respectively (Scheme 2).
Scheme 2
3-{[(2-Sulfanyl-2-sulfido-4-thioxo-1,3,2-benzoxaza-phosphinin-3(4H)yl)imino]methyl}-4H-chromen-4-one (6) and 3-{[2-(4-methoxy-phenyl)-2-sulfido-4-thioxo-1,3,2-benzoxazaphosphinin-3(4H)yl)imino] methyl}-4H-chromen-4-one (7) were obtained in moderate yields from reaction of hydrazone 2 with phosphorus pentasulfide and Lawesson’s reagent, respectively, in dry dioxane for 8−10 hours (Scheme 3).
Scheme 3
We herein report the synthesis of novel 1,3,2-benzoxaza-phosphinines via the ring-closure reactions of hydrazone 2 with some phosphorus halides. Thus, reaction of hydrazone 2 with phosphorus tribromide, phosphorus oxychloride and phenyl phosphonic dichloride in dry dioxane containing two equivalent amounts of triethylamine yielded the corresponding 1,3,2-benzoxaza-phosphininyl chromones 8, 9 and 10, respectively, in good yields (Scheme 4).
Scheme 4
Anticancer activity of the synthesized compounds
The synthesized compounds were evaluated for their anticancer activities against MCF-7 (human breast cancer), HepG2 (human liver cancer), HCT116 (human colon cancer) and PC3 (human prostate cancer) cell lines by SRB assay. Compounds 2, 6, 8 and 10 showed weak anticancer activities. Compounds 4 and 5 that have 1,4,5,2-oxadiaza-phosphinine rings with alkoxy groups, were moderate potent anticancer agents near to the standard drug. Also, compound 9 was the most active one between the 1,3,2-oxazaphosphinine derivatives 8, 9 and 10. The linking of the α-hydrazinophosphonic acid with the chromone moiety in compound 3 played an important role to exhibit the most effect against the MCF-7 cells. Moreover, compound 7 was similar to the reference drug Tamoxifen that may due to the presence of MeOC6H4 moiety attached to the 1,3,2-oxazaphosphininethione moiety.
Inhibitory effect of the synthesized compounds on VEGF
The inhibitory effect of synthesized compounds on the expression of VEGF as a marker for angiogenesis was determined. The results showed that most of the tested compounds showed potent inhibition against expression of VEGF in human breast cancer cell line MCF-7 as compared to the cancer cells. Compounds 3 and 7 were found to be potent inhibitor against expression of VEGF as compared with the positive drug, Tamoxifen. Otherwise, compounds 4, 5 and 9 revealed moderate activities against VEGF. The rest of compounds showed weak activity.
Part II
Reaction of 2-cyano[(4-oxo-4H-chromen-3-yl)methylidene] acetohydrazide with phosphorus reagents: Synthesis and evaluation of anticancer activities of some novel 1,2-azophospholes, 1,2,3-diazaphospholidine and 1,3,2-diazaphosphinanes bearing a chromone ring.
We report here the synthesis of some novel phosphorus heterocycles bearing a chromone ring. The methodology depends on treatment of 2-cyano[(4-oxo-4H-chromon-3-yl)methylidene]acetohydrazide (11) with some phosphorus reagents such as phosphonic acid and its diesters, phosphorus sulfides and phosphorus halides in dry dioxane. The synthesized compounds were examined for their anticancer properties against human breast MCF-7, liver HepG2, colon HCT116 and prostate PC3 cancer cell lines that may act through angiogenesis inhibition. 2-Cyano[(4-oxo-4H-chromen-3-yl) methylidene]acetohydrazide (11) was prepared in good yield by the reaction of 3-formylchromone (1) with cyanoacetohydrazide in absolute ethanol (Scheme 5).
Scheme 5
Compound 11 was reacted with phosphonic acid, and its esters to obtain novel phosphonic acid derivatives bearing a chromone ring. Thus, when compound 11 was allowed to react with phosphonic acid in dry dioxane in the presence of 4-toluenesulfonic acid as a catalyst to give the azaphospholyl chromone derivative 12 in low yield as unexpected product (Scheme 6).
Scheme 6
Similarly, compound 11 was treated with diethyl phosphite and tris(2-chloroethyl)phosphite in the presence of trifluoroboron etherate as a catalyst at 80−90 °C under Pudovik reaction condition to give the dialkyl pyrazolopyrimidine phosphonoates 15 and 16 that were existed in two tautomeric forms 15A,16A (minor forms) and 15B,16B (major forms) (Scheme 7).
Scheme 7
The hydrazone 11 was allowed to react with equivalent amounts of phosphorus sulfides such as phosphorus pentasulfide and Lawesson’s reagent in refluxing dioxane containing a few drops of triethylamine for 4−10 hours. The formed products were a novel class of 1,3,2-diazaphosphinyl chromones 17 and 18, respectively (Scheme 8).
Scheme 8
Treatment of hydrazone 11 with phosphorus tribromide in dry dioxane containing two equivalent amounts of triethylamine gave 3-{[(2-hydroxy-3-imino-2-oxido-5-oxo-1H-1,2-azaphospholidin-1-yl) imino]methyl}-4H-chromen-4-one (19) in moderate yield (Scheme 9).
Scheme 9
In the study, when phosphorus oxychloride was added to a solution of hydrazone 11 in dry dioxane containing two equivalent amounts of triethylamine, the 1,3,2-diazaphosphinyl chromone 20 was obtained in 44% yield (Scheme 10).
Scheme 10
Analogue reaction of the hydrazone 11 with phenyl phosphonic dichloride under the same reaction condition did not lead to construction of product similar to that formed in the case of PBr3 and POCl3. However, this reaction gave one product identified with the 1,2,3-diazaphospholylchromone derivatives 21 (Scheme 11).
Scheme 11
Anticancer activity of the synthesized compounds
The synthesized compounds were evaluated for their anticancer activities against MCF-7 (human breast cancer), HepG2 (human liver cancer), HCT116 (human colon cancer) and PC3 (human prostate cancer) cell lines by SRB assay. Unfortunately, the results revealed that the investigated compounds did not exert any activity against liver HepG2, colon HCT116 and prostate PC3 cells. However, they recorded variable activities against breast MCF-7 cells.
Compounds 11, 15, 16, 17 and 21 showed weak anticancer activities. Moreover, compounds 18 recorded moderate potent anticancer agents near to the standard drug. Compounds 12 and 19 were more potent as anticancer agents against breast MCF-7 cells than the reference drug, Tamoxifen.
Inhibitory effect of the synthesized compounds on VEGF
The inhibitory effect of synthesized compound son the expression of VEGF as a marker for angiogenesis was determined. The results showed that most of the tested compounds showed potent inhibition against expression of VEGF in human breast cancer cell line MCF-7 as compared to the cancer cells. Compounds 12 and 19 were found to be potent inhibitor against expression of VEGF as compared with the positive drug, Tamoxifen. These results were parallel with that of their anticancer activity. Otherwise, compounds 18 and 20 revealed moderate activities against VEGF. The rest of compounds showed weak activity.