الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 220 |  |  |
| | | from | 220 | | |
Abstract
The original work of this thesis comprises three main parts.
Each part has its own numbering of compounds and schemes independent on the other parts
Part I: The synthesis and antineoplastic activities of thiaziridine, sulfidomethylphosphonium, dithiaphos-phitane-sulphide against the Ehrlich ascites carcinoma
Cancer all over the world can lead to death. The main causes of these diseases are related to cell cycle uncontrolled; therefore, it leads to abnormal and successive cell growth. Cancer invasion is related to the alteration of oncogenes, DNA repair genes, and tumor suppressor genes. Cancer puts dangerous restrictions on people health so, the curing and treatment of cancer diseases are still a real challenge. Therefore, many researchers seek the development of novel, more safe, and effective chemo-preventive drugs to face the augmented death rate and the anticancer drug`s reverse effects
On the other hand, organophosphorus compounds are a large category of chemical compounds comprising different organic moieties directly attached to phosphorus or another heteroatom, such as nitrogen, oxygen or sulfur. These compounds are some of the most public chemicals in the environment. Due to their unique properties and high biological activity, they are used along worldwide in pesticides, hydraulic fluids, lubricants and also used in the production of plastics materials, medicinal drugs against osteoporosis, cancer, and viral diseases, or veterinary anthelmintic applications. Recent research findings suggest that a variety of organophosphorus derivatives have potential anticancer properties so, they are used as anticancer drugs.
It was found that ethoxycarbonyltriphenyl phosphinimine (2) reacted with 4-methoxyphenylisothiocyanate (1) in dry boiling toluene for 8 hrs to give ethyl-3-((4-methoxyphenyl)imino)-1,2-thiaziridine-2-carboxylate (4), ethyl(((4-methoxyphenyl)imino)meth-ylene)carbamate (5), 1,2-bis(4-methoxyphenyl)thiourea (6) together with triphenylphosphane and triphenylphosphane sulphide (Scheme 1).
Scheme (1)
When the 3, 4-dichlorophenyl isocyanate (8) was treated with the phosphinimine 2 in boiling toluene for 20 hrs, 1,3-bis (3,4-dichlorophenyl) urea (12) was obtained (Scheme 2).
Scheme (2)
On the other hand, when the reaction of tris(dimethylamino)phosphine (13) with 4-methoxyphenyl isothiocyanate (1) was conducted in THF to form the betaine structure tris (dimethylamino)(((4-methoxyphenyl)imino) sulfide-methyl)phosphonium (14) was obtained (Scheme 3).
Scheme (3)
Moreover, when methyl isothiocyanate (7) was allowed to react with the aminophosphine 13, the corresponding tris(dimethy-lamino)(methyylimino)sulfidomethyl)phosphonium 15 was obtained (Scheme 4).
Scheme (4)
The reaction of 3,4-dichlorophenyl isocyanate (8) with tris(dimethylamino)phosphine (13) gave N’-(3,4-dichlorophenyl)-N,N-dimethylcarbamimidic acid (18) and N,N,N’,N’-tetra-methyl- phosphonic diamide (19) (Scheme 5).
Scheme (5)
Furthermore, the study was extended to include the behavior of 4-methoxyphenyl isothiocyanate (1) towards Lawesson`s reagent (20a). So, when the isothiocyanate 1 was allowed to react with the reagent 20a in refluxing toluene, 2-(4-methoxyphenyl)-4-((4-methoxyphenyl)imino)-1,3,2-dithiaphosphetane-2-sulfide (22) was isolated (Scheme 6).
Scheme (6)
Similarly, when methyl isothiocyanate (7) was reacted with Lawesson`s reagent in dry acetonitrile at room temperature, 2-(4-methoxyphenyl)-4-(methylimino)-1,3,2-dithiaphosphetane-2-sulfide (23) was obtained (Scheme 7).
Scheme (7)
Next, when 3,4-dichlorophenyl isocyanate (8) was allowed to react with Lawesson`s reagent (20) in dry toluene, 4-((3,4-dichlorophenyl)-2-(4-methoxyphenyl)-1,3,2-thiazaphosphetidin-4-one2-sulfide (24) was obtained. On the other hand, when the same reaction was performed in acetonitrile, 4-((3,4-dichlorophenyl)imino)-2-(4-meth-oxyphenyl)-1,3,2-dithiaphosphetane2-sulfide (25) was isolated (Scheme 8).
Scheme (8)
On the other side, when the isothiocyanate 1 was allowed to react with Japanese reagent (26) in THF, the corresponding 4-((4-methoxyphenyl)imino)-2-(phenylthio)-1,3,2-dithiaphosphetane-2-sulfide (27) was obtained (Scheme 9).
Scheme (9)
Similarly, when 3,4-dichlorophenyl isocyanate (8) was reacted with 26 in acetonitrile, 4-((3,4-dichlorophenyl)imino)-2-(phenylthio)-1,3,2-dithiaphosphetane2-sulfide (28) was obtained (Scheme 10).
Scheme (10)
Biology
This study was designed to evaluate the potential anticancer properties of the novel phosphonium and thiophosphate synthesized compounds against Ehrlich ascites tumor in mice. Ehrlich Ascites Carcinoma-bearing mice were employed as an in vivo tumor model because they are extremely undifferentiated and have a rapid growth rate that raising their sensitivity to chemotherapy. The basis for determining the worth of an anticancer medication is the prolongation of life span, the dispose of tumor cells and lessening of tumor size.
In Table 1, the results revealed that the daily treatment of EAC-bearing mice with sulphidomethyl phosphonium, dithiaphosphetane-2-sulphide compounds and 5-Flu for 2 weeks after EAC-cells intraperitoneal transplantation declined the EAC- fluid volume. The reduction exhibited by compounds (14, 15, 18, 25) and 5-Flu was significant (P ≤ 0.05), while, the reduction induced by 23 and 28 compounds was non-significant. Conversely, the count of dead EAC-cells showed a potential increase (P ≤ 0.05) in all treated groups as compared to EAC-bearing control counterparts. Regarding tumor inhibition rate, the six synthesized compounds and a standard anticancer drug 5-Flu induced significant (P ≤ 0.05) tumor inhibition on Ehlich ascites carcinoma cells. There were no significant differences in the aforesaid parameters of sulphidomethyl phosphonium compounds (14, 15) and 5-Fluorouracil used as standard reference anticancer drug. Whereas, there are significant differences between the other tested synthesized compounds and 5-Fluorouracil. This revealed that the sulphidomethyl phosphonium compounds have equivalent antitumor activity as of 5-Flu anticancer drug. While, the thio-dithiaphosphetane-2-sulphide and dithiaphosphetane-2-sulphide compounds were less reactive when compared with 5-Flu. Hence, it may be concluded that the compounds arrest the tumor cell growth, by a direct cytotoxic effect or by decreasing the nutritional fluid volume. These results specify that the compounds have a direct linking with tumor cells as they absorb the anticancer medicine directly in the peritoneal cavity, leading to lysis of the cell via the cytotoxic mechanism.
from results obtained, it is evident that 5-Flurouracil and phosphonium compounds were the more effective compounds and reported that administration of 5-fluorouracil significantly diminished tumor volume compared with EAC-bearing mice. The standard drug, 5-fluorouracil is transformed in the cell into cytotoxic metabolites that are integrated into the nucleic acids, stopping the cell cycle and causing apoptosis. The antitumor activity of the compounds seems to similarly follow this mechanism.
Table 1: Effect of synthesized compounds on EAC volume, alive and dead cell count and tumor inhibition percentage.
Treatments EAC volume (mL) Alive EAC cells (106) Dead EAC cells (106) % Tumor inhibition
EAC 4.17±0.33a 972.00±2.08a 28.00 ±2.08e 2.82±0.20e
5-FL 1.57±0.12e 273.33±39.30e 726.67±39.30a 72.67±3.92a
14 2.30±0.05de 346.67±35.28de 653.33±35.28ab 65.33±3.52ab
15 1.67±0.44e 313.33±32.87e 686.67±32.28a 68.67±3.28a
18 2.80±0.17cd 450.00±28.87cd 550.00±28.87bc 55.00±2.89bc
23 3.87±0.20a 580.00±11.55b 420.00±11.55d 42.00±1.15d
25 3.10±0.21bc 550.00±68.07bc 450.00±68.07cd 45.00±6.81cd
28 3.77±0.19ab 573.33±14.53b 426.67±14.53d 42.67±1.45d
So, the results obtained showed that the 5-Flu and sulphidomethyl phosphonium compounds (14, 15) caused significant elevation (P ≤ 0.05) in the percent of DNA fragmentation in the tissue of EAC-bearing mice. Compounds 18, 28, and 25 displayed non-significant increase in the percentage of DNA fragmentation in EAC-bearing tissue, whereas, compounds 23 induced significant decline (P ≤ 0.05). There were no significant differences in DNA fragmentation percent of 5-Flu and the 14 and 15 compounds treated groups, while, there are significant differences between carbamimidic acid, dithiaphosphetane-2-sulphide compounds and
Data were expressed as mean ± SE. Different superscripts within the same column were representing significant differences (P ≤ 0.05).
thiodithiaphosph-etane-2-sulphide (18, 23, 25 and 28) and 5-Flu group.
Therefore, these compounds have anti antineoplastic activity and have contribution in apoptosis. where the general conclusion was based on the data that treatment with these compounds leads to decreasing tumor volume; increase in tissue DNA fragmentation, downregulation of antiapoptotic gene, and up-regulation of apoptotic markers in liver tissues of EAC-bearing mice. These findings also showed that the sulphidomethyl phosphonium compounds had an antitumor effect comparable to those of the 5-fluorouracil. These compounds could have promising role in the treatment of a variety of malignant tumors.
Part II: Synthesis of Novel Organophosphorus and Organosilane Compounds from the Reaction of Mono-and Di-Phosphorus Reagents.
Organosilanes are important intermediates in the synthesis of many valuable compounds, particularly in pharmaceutical and medicinal chemistry. These compounds are characterized by high resistance to hydrolysis and thermolysis. They are used in fields of heat transmission, fixation of paints and inks, silicon rubber industry, plastics, electric devices and also for coating metallic surfaces.
Organosilicon compounds have many interesting applications especially in medicine as anti-inflammatory, antibacterial, and anticancer agents due to the difference in the chemical properties of molecules containing silicon.
Herein the work was undertaken for the formation of phosphorus-silicon heterocyclic derivatives of various applications. Consequently, the present study aims at studying the reactions of certain isocyanates and isothiocyantes with different organophos-phorus ylides.
Thus, the reaction of trimethylsilyl isocyanate (1) with N-phenyliminovinylidene)triphenylphosphorane (2) upon stirring in dry THF yielded a mixture of N2-phenyl-N4-(trimethylsilyl)-3-(triphenyl-l5-phosphaneylidene)oxetane-2,4-diimine (4) and N4-phenyl-N2-N6-bis(trimethylsilyl)-5-(triphenyl-l5-phosphaneylidene)-1,3-dioxane-2,4,6-triimine (5) (Scheme 1).
Scheme (1)
But, when trimethylsilyl isocyanate (1) was stirred in dry THF with (2-oxovinylidene)triphenylphosphorane (6), 1,3-bis(trimethyl -silyl)-5-(triphenyl-l5-phosphaneylidene)pyrimidine-2,4,6(1H,3H,5H)-trion(8) was obtained (Scheme 2).
Scheme (2)
Next, the reaction of trimethylsilyl isothiocyanate (9) with N-phenyliminovinylidene)-triphenylphosphorane (2) and with (2-oxovinylidene)triphenylphosphorane (6) under good stirring in dry THF, has been investigated. The initially formed dipolar intermediate (10, X= NPh) undergoes then intramolecular rearrangement to gave the four membered structure 4-(phenylimino)-1-(trimethylsilyl)-3-(triphenylphospho-ranylidene)-azetidine-2-thione (11). Meanwhile, the intermediate (10, X=O) gave six-membered ring structure, 2,6-bis(trimethylsilyl)imino)-5-(triphenyl-l5-phosphaneylidene)-1,3-dithian-4-one (12) (Scheme 3).
Scheme (3)
The bis-ylide, hexaphenylcarbodiphosphorane (13) is a nucleophilic reagent, that attracted chemists’ attention for its electronic distribution. Therefore, when hexaphenylcarbodiphosphorane (13) was allowed to react with trimethylsilyl isocyanate (1) in dry THF at room temperature it afforded 2,2,2-triphenyl-1-(trimethylsilyl)-3-(triphenyl-λ5-phosphaneylidene)-1,2-λ5-azaphosphetidin-4-one (15) (Scheme 4).
Scheme (4)
Moreover, upon reacting trimethylsilyl isothiocyanate (9) with hexaphenylcarbodiphosphorane (13), 2,2,2-triphenyl-N-(trimethylsil-yl)-3-(triphenyl-λ5-phosphanylidene)-1,2-λ5-thia-phosphetan-4-imine (17) was isolated (Scheme 5).
Scheme (5)
When isopropyl isocyanate (18) was reacted with diphosphorane 13 in dry toluene, gave the six-membered, 3-isopropyl-6-(isopropyl-imino)-4,4,4-triphenyl-5-(triphenyl-λ5-phosphaneylidene)-1,3,4-λ5-oxazaphosphinan-2-one (20a) together with N,N-diisopropyl urea (20b) (Scheme 6).
Scheme (6)
Moreover, the reaction 3,4-dichlorophenyl isocyanate (21), with hexaphenylcarbodiphosphorane (13) proceeded by stirring in dry THF to afford,1-(3,4-dichlorophenyl)-2,2,2-triphenyl-3-(triphenyl-λ5-phosphoraneylidene)-1,2-λ5-azaphosphetidin-4-one (23), (Scheme 7). Scheme (7)
The reaction of 13 with methyl isothiocyanate (24) gave 1-methyl-2,2,2-triphenyl-3-(triphenyl-λ5-phosphaneylidene)-1,2-λ5-azaphosph-etidin-4-thione (26) (Scheme 8).
Scheme (8)
Phenyl isothiocyanate (27) was refluxed with hexa-phenylcarbodiphosphorane (13) in dry toluene to give three products,N,2,2,2-tetraphenyl-3-(triphenyl-λ5-phosphaneylidene)-1,2-λ5-thiaphosphetan-4-imine (29a). The second product is 3,4,4,4-tetraphenyl-6-(phenylimino)-5-(triphenyl-λ5-phosphaneylidene)-1,3, 4-λ5-thiazaphosphinane-2-thione (29b). The third compound is 1,3-N,N`-diphenyl thiourea (29c) (Scheme 9).
Scheme (9)
Part III: A convenient Synthesis of New Azetidine-, Pyrimidine-, Thietane-and Thiazinane-Phosphoranylidene Derivatives, from the reaction of Iso(thio)cyanates with Phosphorus reagents.
Heterocyclic compounds containing nitrogen and sulfur always draw much attention for researchers of organic and medicinal chemistry during the last decades. The most important structure units of biological activities are N-containing heterocycles such as azitidine, oxazine, pyrimidine. Heterocyles containing azetidine moiety exhibit diversity of pharmacological properties, as antimicrobial, antiviral, analgesic, anti-inflammatory, antimalarial, antiobesity, antidiabetic, and anticancer.
Reactions of isocyanate and isothiocyanate with heterocumulene ylides are interesting mechanistically and synthetically due to the varying periselectivity to form four and six-membered cycloadducts. When isopropyl isocyanate (1) was refluxed with N-phenylimino-vinylidene)-triphenylphosphorane (2a) in dry toluene three products were obtained. The first four-membered ring product, 1-isopropyl-4-(phenylimino)-3-(triphenyl-5-phosphaneylidene)azetidin-2-one(4a). The other two products are a six-membered ring, 1,3-diisopropyl-6-(phenylimino)-5-(triphenyl-5-phosphaneylidene)dihydropyrimidine-2,4(1H,3H)-dione (5) and 3-isopropyl-2-(isopropylimino)-6-(phenyl-imino)-5-(triphenylphosphoranylide-ne)-1,3-oxazinan-4-one (6) were obtained.
On the other hand, when isopropyl isocyanate was stirred with (2-oxovinylidene)triphenylphosphorane (2b) in dry THF gave the four-membered ring, 1-isopropyl-3-(triphenyl-λ5-phosphaneylidene)-azet-idine-2,4-dione (4b) (Scheme 1).
Scheme (1)
Moreover, the reaction of phenyl isothiocyanate (7) with N-phenyliminovinylidene)triphenylphosphorane (2a) in dry toluene undr reflux gave three products, too. These products were four membered ring, N2,N4-diphenyl-3-(triphenyl-5-phosphaneylidene)-thietane-2,4-diimine (9), the second product is 3-phenyl-4,6-bis(phenylimino)-5-(triphenyl-5-phosphaneylidene)-1,3-thiazinane-2-thione (10) and the third product N2,N4,N6-triphenyl-5-(triphenyl-λ5-phosphaneylidene)-1,3-dithiane-2,4,6-triimine (11) (Scheme 2).
Scheme (2)
When phenyl isothiocyante (7) was allowed to react with (2-oxovinylidene)triphenylphosphorane (2b) gave three different products were obtained. The first product formed by refluxing in dry toluene 1-phenyl-4-thioxo-3-(triphenyl-5-phosphaneylidene)azetid-in-2-one (13). Moreover, When the reaction was repeated in dry THF, other two products, 4-(phenylimino)-3-(triphenyl-5-phosphaneylidene)-thietan-2-one (14), and 2,6-bis(phenylimino)-5-(triphenyl-5-phos-phaneylidene)-1,3-dithian-4-one (15) were isolated, too (Scheme 3).
Scheme (3)
On the other side, the reactions of stabilized phosphonium ylides (16a, 16b) with isopropyl isocyanate (1) and phenyl isothiocyanate (7) were also investigated to make a comparison of ylides activities and site of attack determining the mode of reaction. Thus, reaction of methoxycarbonyl-(16a), ethoxycarbonyltriphenylphosphorane (16b) with isocyanate 1 and isothiocyanate 7 were conducted in dry THF to give the new phosphorane derivatives (18a-d) which were formed via the intermediacy of the betaines (17a-d) (Scheme 4).
Scheme (4)
Moreover, the study was extended to cover the reaction of hexamethyltriaminophosphine (19) with isocyanate 1 in dry THF whereby, N’-isopropyl-N,N-dimethylcarbamimidic acid (22) was formed (Scheme 5).
Scheme (5)
In addition, the reaction of phenyl isothiocyanate (7) with 19 gave stable phosphonium betaine 23 (Scheme 6).
Scheme (6)