Applications of Baylis-Idllman methodology in the synthesis of chromene derivatives
- Authors: Nocanda, Xolani Wittleton
- Date: 2001
- Subjects: Heterocyclic chemistry , Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4556 , http://hdl.handle.net/10962/d1018257
- Description: The reaction of salicylaldehyde with various activated alkenes, viz., methyl vinyl ketone, ethyl vinyl ketone, phenyl vinyl sulfone, phenyl vinylsulfonate, acrolein and acrylonitrile, under Baylis-Hillman conditions, has been found to proceed with the chemoselective formation of chromene derivatives. The reaction conditions have been optimised and chromene derivatives have been obtained in isolated yields up to 87 %. The generality of the reaction, using 1,4-diazabicyclo[2.2.2]octane (DABCO), as the catalyst, and a heterogeneous (chloroform-water) solvent system, has been established using a range of salicylaldehyde derivatives,. including 2-hydroxynaphthaldehyde. The formation of chromene derivatives, under these conditions, has been assumed to proceed via an initial, Baylis-Hillman reaction, followed by cyclisation involving intramolecular conjugate addition, and subsequent dehydration. Evidence supporting this sequence has been obtained from the isolation ofBaylis-Hillman products from reactions involving the use of tertbutylclimethylsilyl-protected salicylaldehyde, 4-hydroxybenzaldehyde and tert-butyl acrylate as substrates. The potential of the ''Baylis-Hillman zwitterion" to participate as a donor species in Michael-type addition reactions has been explored and a series of climeric products has been isolated. The Baylis-Hillman methodology has also been successfully extended to the synthesis of sulfurcontaining heterocyclic systems, and a range of 3-substituted thiochromenes has been obtained in moderate yields, using 2,2'-dithiobenzaldehyde and various activated alkenes in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst. The electron-impact mass spectra of selected chromene and thiocbromene derivatives have been investigated permitting comparison of the fragmentation of the oxygen- and sulfur-containing analogues. In a study directed at the synthesis of potential HIV -1 protease inhibitors, chromene- and thiocbromene-containing analogues of the clinically useful drug, ritonavir, have been prepared. Thiochromene and chromene derivatives were converted to the corresponding 3 -carboxylic acids and coupled with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing cbromene and thiochromene termini in ca. 60% yield.
- Full Text:
- Date Issued: 2001
- Authors: Nocanda, Xolani Wittleton
- Date: 2001
- Subjects: Heterocyclic chemistry , Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4556 , http://hdl.handle.net/10962/d1018257
- Description: The reaction of salicylaldehyde with various activated alkenes, viz., methyl vinyl ketone, ethyl vinyl ketone, phenyl vinyl sulfone, phenyl vinylsulfonate, acrolein and acrylonitrile, under Baylis-Hillman conditions, has been found to proceed with the chemoselective formation of chromene derivatives. The reaction conditions have been optimised and chromene derivatives have been obtained in isolated yields up to 87 %. The generality of the reaction, using 1,4-diazabicyclo[2.2.2]octane (DABCO), as the catalyst, and a heterogeneous (chloroform-water) solvent system, has been established using a range of salicylaldehyde derivatives,. including 2-hydroxynaphthaldehyde. The formation of chromene derivatives, under these conditions, has been assumed to proceed via an initial, Baylis-Hillman reaction, followed by cyclisation involving intramolecular conjugate addition, and subsequent dehydration. Evidence supporting this sequence has been obtained from the isolation ofBaylis-Hillman products from reactions involving the use of tertbutylclimethylsilyl-protected salicylaldehyde, 4-hydroxybenzaldehyde and tert-butyl acrylate as substrates. The potential of the ''Baylis-Hillman zwitterion" to participate as a donor species in Michael-type addition reactions has been explored and a series of climeric products has been isolated. The Baylis-Hillman methodology has also been successfully extended to the synthesis of sulfurcontaining heterocyclic systems, and a range of 3-substituted thiochromenes has been obtained in moderate yields, using 2,2'-dithiobenzaldehyde and various activated alkenes in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst. The electron-impact mass spectra of selected chromene and thiocbromene derivatives have been investigated permitting comparison of the fragmentation of the oxygen- and sulfur-containing analogues. In a study directed at the synthesis of potential HIV -1 protease inhibitors, chromene- and thiocbromene-containing analogues of the clinically useful drug, ritonavir, have been prepared. Thiochromene and chromene derivatives were converted to the corresponding 3 -carboxylic acids and coupled with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing cbromene and thiochromene termini in ca. 60% yield.
- Full Text:
- Date Issued: 2001
Chemical studies of chromone derivatives
- Authors: Sabbagh, Liezel Veronica
- Date: 2001
- Subjects: Benzopyrans Heterocyclic compounds -- Derivatives Coumarins
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4424 , http://hdl.handle.net/10962/d1006899
- Description:
This study has focussed on several aspects of chromone chemistry, viz., (i) the influence of remote substituents on the basicity of 2-(N,N-dimethylamino)chromones, (ii) MoritaBaylis-Hillman reactions of substituted chromone-3-carbaldehydes and (iii) an investigation into the application of chromone chemistry in the total synthesis of the marine natural product, Rietone A. Selected 2-(N,N-dimethylamino )chromones were prepared using two different methods; firstly, via cyclisation of salicylate-derived N,N-dimethyl-3;.(2-hydroxyphenyl)-3- oxopropanamide precursors and, secondly, via 2-hydroxyacetophenone boron difluoride complexes. ¹³C NMR analysis of the 6- and 7-methoxy-2-(N,N-dimethylamino)chromones confirmed that protonation occurs at the chromone carbonyl oxygen rather than the amino nitrogen - a conclusion supported by mol~cular orbital calculations. Potentiometric analysis of 2-(N,N-dimethylamino )chromones in ethanol-water afforded pKa (pK [subscript a]) values in the range 2.22 - 2.52. The observed trend has been rationalised in terms of substituent effects with the aid of molecular orbital calculations at the semi-empirical and ab initio levels, while hydrogen-bonding effects have been used to account for the apparently anomalous result obtained for the 6-nitro derivative. A series of seven substituted chromone-3-carbaldehydes, prepared by the application of Vilsmeier-Haack methodology to the corresponding 2-hydroxyacetophenones, have been examined as substrates for Morita-Baylis-Hillman reactions, using DABCO as the catalyst and three different activated alkenes, viz., methyl acrylate, methyl vinyl ketone and acrylonitrile. In all cases, with the exception of 6-nitrochromone-3-carbaldehyde, the reactions have been shown to afford the expected Morita-Baylis-Hillman products. Use of methyl acrylate and methyl vinyl ketone as the activated alkene has been observed to afford additional, unprecedented dimeric products, which have been unambiguously characterised using a combination of single crystal X-ray analysis and spectroscopic (high resolution MS and NMR) techniques. Different dimer-like adducts have been isolated from reactions in which acrylonitrile was used as the activated alkene, and the structures of these novel products have-been determined
- Full Text:
- Date Issued: 2001
- Authors: Sabbagh, Liezel Veronica
- Date: 2001
- Subjects: Benzopyrans Heterocyclic compounds -- Derivatives Coumarins
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4424 , http://hdl.handle.net/10962/d1006899
- Description:
This study has focussed on several aspects of chromone chemistry, viz., (i) the influence of remote substituents on the basicity of 2-(N,N-dimethylamino)chromones, (ii) MoritaBaylis-Hillman reactions of substituted chromone-3-carbaldehydes and (iii) an investigation into the application of chromone chemistry in the total synthesis of the marine natural product, Rietone A. Selected 2-(N,N-dimethylamino )chromones were prepared using two different methods; firstly, via cyclisation of salicylate-derived N,N-dimethyl-3;.(2-hydroxyphenyl)-3- oxopropanamide precursors and, secondly, via 2-hydroxyacetophenone boron difluoride complexes. ¹³C NMR analysis of the 6- and 7-methoxy-2-(N,N-dimethylamino)chromones confirmed that protonation occurs at the chromone carbonyl oxygen rather than the amino nitrogen - a conclusion supported by mol~cular orbital calculations. Potentiometric analysis of 2-(N,N-dimethylamino )chromones in ethanol-water afforded pKa (pK [subscript a]) values in the range 2.22 - 2.52. The observed trend has been rationalised in terms of substituent effects with the aid of molecular orbital calculations at the semi-empirical and ab initio levels, while hydrogen-bonding effects have been used to account for the apparently anomalous result obtained for the 6-nitro derivative. A series of seven substituted chromone-3-carbaldehydes, prepared by the application of Vilsmeier-Haack methodology to the corresponding 2-hydroxyacetophenones, have been examined as substrates for Morita-Baylis-Hillman reactions, using DABCO as the catalyst and three different activated alkenes, viz., methyl acrylate, methyl vinyl ketone and acrylonitrile. In all cases, with the exception of 6-nitrochromone-3-carbaldehyde, the reactions have been shown to afford the expected Morita-Baylis-Hillman products. Use of methyl acrylate and methyl vinyl ketone as the activated alkene has been observed to afford additional, unprecedented dimeric products, which have been unambiguously characterised using a combination of single crystal X-ray analysis and spectroscopic (high resolution MS and NMR) techniques. Different dimer-like adducts have been isolated from reactions in which acrylonitrile was used as the activated alkene, and the structures of these novel products have-been determined
- Full Text:
- Date Issued: 2001
Design, synthesis and evaluation of silver-specific ligands
- Authors: Daubinet, André
- Date: 2001
- Subjects: Ligands Ligands -- Design Ligands -- Analysis Ligands -- Evaluation Silver -- Metallurgy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4308 , http://hdl.handle.net/10962/d1004966
- Description: Several series of ligands, designed to chelate silver(I) specifically in the presence of base metals, have been synthesised. The ligands include: - dithiodiamide compounds, prepared by the condensation of acetanilide derivatives with 1,2-dibromoethane; propanenitrile and propanoic ester derivatives prepared from pyridine-2-carbaldehyde via the Morita-Baylis-Hillman reaction; and novel malonamide ligands from the reaction of diethyl malonate with a range of primary amines. The malonamide derivatives were prepared under both conventional thermal and microwave-assisted conditions, the latter proving to be highly efficient. The ligands were all characterised using a combination of spectroscopic and, where appropriate, elemental analysis; in one case, the structural assignment was confirmed by single-crystal X-ray analysis. The fragmentation patterns in the electron-impact mass spectra of the malonamide derivatives have been explored using high-resolution and meta-stable peak scanning techniques. Complexes of the malonamide ligands with copper(II) and silver(I) have been synthesised, and examination of these complexes has revealed distinct differences in their co-ordination preferences towards silver(I) and copper(II). Tentative, computer-modelled structures for the complexes have been proposed using the available spectroscopic and elemental analysis data. Computer modelling, at the Molecular Mechanics level, has also been used to assess the capacity of the ligand systems to adopt conformations suitable for the chelation of tetrahedral silver(I). Solvent extraction studies have been undertaken using aqueous metal ion solutions and various organic solvents. The dithiodiamide derivatives typically presented solubility problems, but one of the ligands, N,N´-bis(3-chlorophenyl)-3,6-dithiaoctanediamide, exhibited significant but slow extraction of silver(I) into toluene. The malonamide derivatives, however, proved to be readily soluble in ethyl acetate and, in some cases, exhibited good to excellent selectivity for silver(I) in the presence of the base metals copper and lead. Atomic absorption analysis revealed rapid equilibration times (<15 min) and high extraction efficiencies over a wide pH range (2.78 - 9.0). Metal selectivity has been determined by ICP-MS analysis of the residual silver, copper and lead present in the aqueous phase after 15 min, and one of the ligands, N,N´-bis(2-benzylsulfanylethyl)malonamide, exhibits excellent (≥ 96 %) silver(I) specificity.
- Full Text:
- Date Issued: 2001
- Authors: Daubinet, André
- Date: 2001
- Subjects: Ligands Ligands -- Design Ligands -- Analysis Ligands -- Evaluation Silver -- Metallurgy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4308 , http://hdl.handle.net/10962/d1004966
- Description: Several series of ligands, designed to chelate silver(I) specifically in the presence of base metals, have been synthesised. The ligands include: - dithiodiamide compounds, prepared by the condensation of acetanilide derivatives with 1,2-dibromoethane; propanenitrile and propanoic ester derivatives prepared from pyridine-2-carbaldehyde via the Morita-Baylis-Hillman reaction; and novel malonamide ligands from the reaction of diethyl malonate with a range of primary amines. The malonamide derivatives were prepared under both conventional thermal and microwave-assisted conditions, the latter proving to be highly efficient. The ligands were all characterised using a combination of spectroscopic and, where appropriate, elemental analysis; in one case, the structural assignment was confirmed by single-crystal X-ray analysis. The fragmentation patterns in the electron-impact mass spectra of the malonamide derivatives have been explored using high-resolution and meta-stable peak scanning techniques. Complexes of the malonamide ligands with copper(II) and silver(I) have been synthesised, and examination of these complexes has revealed distinct differences in their co-ordination preferences towards silver(I) and copper(II). Tentative, computer-modelled structures for the complexes have been proposed using the available spectroscopic and elemental analysis data. Computer modelling, at the Molecular Mechanics level, has also been used to assess the capacity of the ligand systems to adopt conformations suitable for the chelation of tetrahedral silver(I). Solvent extraction studies have been undertaken using aqueous metal ion solutions and various organic solvents. The dithiodiamide derivatives typically presented solubility problems, but one of the ligands, N,N´-bis(3-chlorophenyl)-3,6-dithiaoctanediamide, exhibited significant but slow extraction of silver(I) into toluene. The malonamide derivatives, however, proved to be readily soluble in ethyl acetate and, in some cases, exhibited good to excellent selectivity for silver(I) in the presence of the base metals copper and lead. Atomic absorption analysis revealed rapid equilibration times (<15 min) and high extraction efficiencies over a wide pH range (2.78 - 9.0). Metal selectivity has been determined by ICP-MS analysis of the residual silver, copper and lead present in the aqueous phase after 15 min, and one of the ligands, N,N´-bis(2-benzylsulfanylethyl)malonamide, exhibits excellent (≥ 96 %) silver(I) specificity.
- Full Text:
- Date Issued: 2001
Extractives from six species of South African Marine Opisthobranch Molluscs
- Authors: McPhail, Kerry Lee
- Date: 2001
- Subjects: Mollusks -- Nutrition Mollusks -- Anatomy Marine fishes -- South Africa
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4433 , http://hdl.handle.net/10962/d1007412
- Description: The natural product chemistry of six species of South African opisthobranch molluscs and some of their dietary marine invertebrates was investigated. Nineteen previously undescribed secondary metabolites and twelve known compounds were isolated and their structures determined by a combination of spectroscopic and chemical methods. The circumtropical sea hares Aplysia parvula and A. dactylomela were found to contain halogenated red algal metabolites. 3Z-bromofucin (120), the Z analogue of a known Laurencia CIS acetogenin, was isolated from A. parvula. A. dactylomela yielded a series of novel non-aromatic cuparanes, the algoanes (121-123), the novel tricyclic Iaurane ether ibhayinol (124) and three known chamigrane sesquiterpenes, prepacifenol epoxide (101), pacif-7-enediol (104) and nidificene (125). A variety of new octocoral sesquiterpenes were isolated from the endemic South African arminacean nudibranch Leminda millecra including algoafuran (150), cubebenone (151), 8-hydroxycalamenene (152) and a series of seven triprenylated toluquinones and toluquinols (153-159). L. millecra also yielded the known sesquiterpenes millecrones A (142) and B (143) and isofuranodiene (149). Twenty eight voucher specimens and eighteen crude extracts of South African octocorals collected by the Coral Reef Research Foundation were screened by GC and GC-MS and 142 was found in Alcyonium fauri, while 143, 151 and possibly 149 were present in Leptogorgia palma. An investigation of southern African chromodorids yielded the known macrocyc1e latrunculin B (220) and two new spongiane diterpenes (221) and (222) from Chromodoris hamiltoni, while the known spongiane diterpene (210) was isolated from the endemic nudibranch Glossodoris sp. 4. The endemic nudibranch Hypselodoris capensis contained the known furanosesquiterpenes nakafuran-8 (223) and -9 (224) and the known furanosesterterpenes variabilin (195), 22-deoxyvariabilin (225) and furospinosulin (227) together with the new variant 22-deoxy-23-hydroxymethylvariabilin (226). Compounds 223 and 224 were also found in a Dysidea sponge, while the furanosesterterpenes 195, and 225-227 were present in a Fasciospongia sponge upon which H capensis specimens were found. The Dysidea dietary sponge of H capensis also yielded a new aromatic sesquiterpene, tsitsikarnmafuran (266), whose structure was confirmed by the synthesis of two possible regioisomers.
- Full Text:
- Date Issued: 2001
- Authors: McPhail, Kerry Lee
- Date: 2001
- Subjects: Mollusks -- Nutrition Mollusks -- Anatomy Marine fishes -- South Africa
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4433 , http://hdl.handle.net/10962/d1007412
- Description: The natural product chemistry of six species of South African opisthobranch molluscs and some of their dietary marine invertebrates was investigated. Nineteen previously undescribed secondary metabolites and twelve known compounds were isolated and their structures determined by a combination of spectroscopic and chemical methods. The circumtropical sea hares Aplysia parvula and A. dactylomela were found to contain halogenated red algal metabolites. 3Z-bromofucin (120), the Z analogue of a known Laurencia CIS acetogenin, was isolated from A. parvula. A. dactylomela yielded a series of novel non-aromatic cuparanes, the algoanes (121-123), the novel tricyclic Iaurane ether ibhayinol (124) and three known chamigrane sesquiterpenes, prepacifenol epoxide (101), pacif-7-enediol (104) and nidificene (125). A variety of new octocoral sesquiterpenes were isolated from the endemic South African arminacean nudibranch Leminda millecra including algoafuran (150), cubebenone (151), 8-hydroxycalamenene (152) and a series of seven triprenylated toluquinones and toluquinols (153-159). L. millecra also yielded the known sesquiterpenes millecrones A (142) and B (143) and isofuranodiene (149). Twenty eight voucher specimens and eighteen crude extracts of South African octocorals collected by the Coral Reef Research Foundation were screened by GC and GC-MS and 142 was found in Alcyonium fauri, while 143, 151 and possibly 149 were present in Leptogorgia palma. An investigation of southern African chromodorids yielded the known macrocyc1e latrunculin B (220) and two new spongiane diterpenes (221) and (222) from Chromodoris hamiltoni, while the known spongiane diterpene (210) was isolated from the endemic nudibranch Glossodoris sp. 4. The endemic nudibranch Hypselodoris capensis contained the known furanosesquiterpenes nakafuran-8 (223) and -9 (224) and the known furanosesterterpenes variabilin (195), 22-deoxyvariabilin (225) and furospinosulin (227) together with the new variant 22-deoxy-23-hydroxymethylvariabilin (226). Compounds 223 and 224 were also found in a Dysidea sponge, while the furanosesterterpenes 195, and 225-227 were present in a Fasciospongia sponge upon which H capensis specimens were found. The Dysidea dietary sponge of H capensis also yielded a new aromatic sesquiterpene, tsitsikarnmafuran (266), whose structure was confirmed by the synthesis of two possible regioisomers.
- Full Text:
- Date Issued: 2001
Synthesis and characterisation of novel platinum (II) complexes potential chemotherapeutic drugs
- Authors: Datt, Michael Steven
- Date: 2001
- Subjects: Chemotherapy Platinum
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4366 , http://hdl.handle.net/10962/d1005031
- Description: The present study involves the preparation of novel mixed-ligand platinum(II) complexes in the hope of expanding the range of platinum(II) complexes that exhibit anticancer activity and which are less toxic and have a broader spectrum of activity than cisplatin and its analogues. To this end, N-(3-R-benzoyl)-N’,N’-diethylthiourea, N-(3-R-benzoyl)-N’-morpholinothiourea, N-(3-Rbenzoyl)-N’,N’-di(2-hydroxyethyl)thiourea (R = NO2, Cl, H, CH3, OCH3), N,N-diethyl-N’-menthyloxycarbonylthiourea and N-menthyloxycarbonyl-N’-morpholinothiourea ligands, and their corresponding mixed-ligand platinum(II) complexes of the type [PtCl(L)(RR’SO)], were synthesised and characterised by elemental analyses, IR, 1H and 195Pt NMR spectroscopy and, in some cases, X-ray crystallography. Dimethylsulfoxide complexes were prepared using all the ligands, while complexes containing unsymmetrically substituted sulfoxides were prepared using the N-benzoyl-N’,N’-diethylthiourea and ,N-diethyl-’-(-)-(3R)-menthyloxycarbonylthiourea ligands only. The molecular structures of cis-(S,S)-[PtCl(DMSO)(L)] (where L = N-benzoyl-N’,N’-diethylthioureato, N-(+)-(3S)-menthyloxycarbonyl-N’-morpholinothioureato), cis-(S,S)-[Pt(N-benzoyl-N’,N’-diethylthioureato)Cl(MPSO)] and cis-[Pt(N-benzoyl-N’,N’-diethylthioureato)2] were determined by X-ray crystallography. The X-ray crystal structure of N,N-diethyl-N’- (-)-(3R)-menthyloxycarbonylthiourea was also determined. The spectroscopic and crystallographic data are consistent with complexes containing a (S,O)-chelated ligand and a sulfur-bonded sulfoxide ligand. However, the 1H and 195Pt NMR studies showed that the alkoxycarbonylthioureato complexes exist as geometric isomers with the sulfoxide coordinated either in a cis-(S,S) or trans-(S,S) arrangement with respect to the sulfur donor atom of the chelated ligand, whereas the acylthioureato complexes yielded only cis-(S,S)-[PtCl(L)(RR’SO)] complexes. The difference in the coordination chemistry of the acylthiourea and alkoxycarbonylthiourea ligands was examined further by treatment of the [PtCl(DMSO)(L)] complexes, where L = Nbenzoyl-N’,N’-diethylthioureato, N-benzoyl-N’-morpholinothioureato, N,N-diethyl-N’-(-)-(3R)- menthyloxycarbonylthioureato and N-(+)-(3S)-menthyloxycarbonyl-N’-morpholinothioureato, with PPh3 to give the corresponding [PtCl(L)(PPh3)] and [Pt(L)(PPh3)2]+ complexes. 31P NMR studies of these complexes reveal that the alkoxycarbonylthioureato ligands bind less strongly than the acylthioureato ligands, which is consistent with the crystallographic studies. The morpholine derivatives of the acylthioureato and alkoxycarbonylthioureato ligand systems also appear to bind less tightly than the diethyl derivatives. The weaker binding properties of the alkoxycarbonylthioureato ligands might be a possible explanation for the observed geometric isomerisation of these complexes, with the mechanism of isomerisation involving a chelate ringiv opening step. Furthermore, crystallographic and 31P NMR studies suggest that the acylthioureato carbonyl oxygen donor atom is relatively softer and therefore has a greater trans-influence than the carbonyl oxygen donor atom of the alkoxycarbonylthioureato ligand. The substitution kinetics of the chloride and sulfoxide leaving groups by azide, iodide, thiocyanate, triphenylphosphine, 2-mercaptobenzimidazole, 4-(dimethylamino)pyridine and thiourea, from selected cis-(S,S)-[PtCl(N,N-dialkyl-N’-(3-R-benzoyl)thioureato)(RR’SO)] complexes, in methanol, were evaluated to determine if variation of the electronic properties of the chelated ligand and variation of the sulfoxide have a significant influence on the reactivity of these complexes. Two consecutive reactions were observed. It was found that neutral nucleophiles initially substitute the dimethylsulfoxide, while anionic nucleophiles substituted the chloride ligand. For all the nucleophiles studied, the first substitution step was evaluated, except for triphenylphosphine and 4-(dimethylamino)pyridine, where the second step was also evaluated. The overall order of reactivity for the first substitution step was; N3 - < DMAP < I- < SCN- < MBI < thiourea < PPh3, with the rate varying three orders of magnitude. The substitution of the dimethylsulfoxide ligand by PPh3 from cis-(S,S)-[Pt(N-benzoyl-N’,N’-diethylthioureato)Cl-(DMSO)] to form cis-(S,P)-[Pt(N-benzoyl-N’,N’-diethylthioureato)Cl(PPh3)] was confirmed by X-ray crystallography. In general, manipulation of the chelating moiety, as well as interchanging the sulfoxide did not alter the reactivity of these complexes to a great extent. The anticancer activity of all the platinum(II) sulfoxide complexes were evaluated against a HeLa cell line, of which three complexes, cis-(S,S)-[PtCl(DMSO)(N,N-diethyl-N’-(3-nitrobenzoyl)- thioureato)], cis-(S,S)-[PtCl(DMSO)(N-morpholino-N’-(3-nitrorobenzoyl)thioureato)] and cis-(S,S)-[PtCl(DMSO)(N-(3-methoxybenzoyl)-N’-morpholinothioureato)] exhibited a concentration dependent anti-proliferative effect, but were less potent than cisplatin. These three complexes displayed a similar dose response in a MCF-7 cell line. Preliminary morphology studies with the three biologically active complexes in a HeLa cell line suggest that they induce cell death by apoptosis. Preliminary pBR322 plasmid DNA binding studies of selected [Pt(acylthioureato)Cl(RR’SO)]complexes clearly indicate that these complexes have a different mode of binding to DNA than cisplatin.
- Full Text:
- Date Issued: 2001
- Authors: Datt, Michael Steven
- Date: 2001
- Subjects: Chemotherapy Platinum
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4366 , http://hdl.handle.net/10962/d1005031
- Description: The present study involves the preparation of novel mixed-ligand platinum(II) complexes in the hope of expanding the range of platinum(II) complexes that exhibit anticancer activity and which are less toxic and have a broader spectrum of activity than cisplatin and its analogues. To this end, N-(3-R-benzoyl)-N’,N’-diethylthiourea, N-(3-R-benzoyl)-N’-morpholinothiourea, N-(3-Rbenzoyl)-N’,N’-di(2-hydroxyethyl)thiourea (R = NO2, Cl, H, CH3, OCH3), N,N-diethyl-N’-menthyloxycarbonylthiourea and N-menthyloxycarbonyl-N’-morpholinothiourea ligands, and their corresponding mixed-ligand platinum(II) complexes of the type [PtCl(L)(RR’SO)], were synthesised and characterised by elemental analyses, IR, 1H and 195Pt NMR spectroscopy and, in some cases, X-ray crystallography. Dimethylsulfoxide complexes were prepared using all the ligands, while complexes containing unsymmetrically substituted sulfoxides were prepared using the N-benzoyl-N’,N’-diethylthiourea and ,N-diethyl-’-(-)-(3R)-menthyloxycarbonylthiourea ligands only. The molecular structures of cis-(S,S)-[PtCl(DMSO)(L)] (where L = N-benzoyl-N’,N’-diethylthioureato, N-(+)-(3S)-menthyloxycarbonyl-N’-morpholinothioureato), cis-(S,S)-[Pt(N-benzoyl-N’,N’-diethylthioureato)Cl(MPSO)] and cis-[Pt(N-benzoyl-N’,N’-diethylthioureato)2] were determined by X-ray crystallography. The X-ray crystal structure of N,N-diethyl-N’- (-)-(3R)-menthyloxycarbonylthiourea was also determined. The spectroscopic and crystallographic data are consistent with complexes containing a (S,O)-chelated ligand and a sulfur-bonded sulfoxide ligand. However, the 1H and 195Pt NMR studies showed that the alkoxycarbonylthioureato complexes exist as geometric isomers with the sulfoxide coordinated either in a cis-(S,S) or trans-(S,S) arrangement with respect to the sulfur donor atom of the chelated ligand, whereas the acylthioureato complexes yielded only cis-(S,S)-[PtCl(L)(RR’SO)] complexes. The difference in the coordination chemistry of the acylthiourea and alkoxycarbonylthiourea ligands was examined further by treatment of the [PtCl(DMSO)(L)] complexes, where L = Nbenzoyl-N’,N’-diethylthioureato, N-benzoyl-N’-morpholinothioureato, N,N-diethyl-N’-(-)-(3R)- menthyloxycarbonylthioureato and N-(+)-(3S)-menthyloxycarbonyl-N’-morpholinothioureato, with PPh3 to give the corresponding [PtCl(L)(PPh3)] and [Pt(L)(PPh3)2]+ complexes. 31P NMR studies of these complexes reveal that the alkoxycarbonylthioureato ligands bind less strongly than the acylthioureato ligands, which is consistent with the crystallographic studies. The morpholine derivatives of the acylthioureato and alkoxycarbonylthioureato ligand systems also appear to bind less tightly than the diethyl derivatives. The weaker binding properties of the alkoxycarbonylthioureato ligands might be a possible explanation for the observed geometric isomerisation of these complexes, with the mechanism of isomerisation involving a chelate ringiv opening step. Furthermore, crystallographic and 31P NMR studies suggest that the acylthioureato carbonyl oxygen donor atom is relatively softer and therefore has a greater trans-influence than the carbonyl oxygen donor atom of the alkoxycarbonylthioureato ligand. The substitution kinetics of the chloride and sulfoxide leaving groups by azide, iodide, thiocyanate, triphenylphosphine, 2-mercaptobenzimidazole, 4-(dimethylamino)pyridine and thiourea, from selected cis-(S,S)-[PtCl(N,N-dialkyl-N’-(3-R-benzoyl)thioureato)(RR’SO)] complexes, in methanol, were evaluated to determine if variation of the electronic properties of the chelated ligand and variation of the sulfoxide have a significant influence on the reactivity of these complexes. Two consecutive reactions were observed. It was found that neutral nucleophiles initially substitute the dimethylsulfoxide, while anionic nucleophiles substituted the chloride ligand. For all the nucleophiles studied, the first substitution step was evaluated, except for triphenylphosphine and 4-(dimethylamino)pyridine, where the second step was also evaluated. The overall order of reactivity for the first substitution step was; N3 - < DMAP < I- < SCN- < MBI < thiourea < PPh3, with the rate varying three orders of magnitude. The substitution of the dimethylsulfoxide ligand by PPh3 from cis-(S,S)-[Pt(N-benzoyl-N’,N’-diethylthioureato)Cl-(DMSO)] to form cis-(S,P)-[Pt(N-benzoyl-N’,N’-diethylthioureato)Cl(PPh3)] was confirmed by X-ray crystallography. In general, manipulation of the chelating moiety, as well as interchanging the sulfoxide did not alter the reactivity of these complexes to a great extent. The anticancer activity of all the platinum(II) sulfoxide complexes were evaluated against a HeLa cell line, of which three complexes, cis-(S,S)-[PtCl(DMSO)(N,N-diethyl-N’-(3-nitrobenzoyl)- thioureato)], cis-(S,S)-[PtCl(DMSO)(N-morpholino-N’-(3-nitrorobenzoyl)thioureato)] and cis-(S,S)-[PtCl(DMSO)(N-(3-methoxybenzoyl)-N’-morpholinothioureato)] exhibited a concentration dependent anti-proliferative effect, but were less potent than cisplatin. These three complexes displayed a similar dose response in a MCF-7 cell line. Preliminary morphology studies with the three biologically active complexes in a HeLa cell line suggest that they induce cell death by apoptosis. Preliminary pBR322 plasmid DNA binding studies of selected [Pt(acylthioureato)Cl(RR’SO)]complexes clearly indicate that these complexes have a different mode of binding to DNA than cisplatin.
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- Date Issued: 2001
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