Metallocene antitumor agents. Solution and solid-state molybdenocene coordination chemistry of DNA constituents

Louis Y. Kuo, Mercouri G Kanatzidis, Michal Sabat, Andrew L. Tipton, Tobin J Marks

Research output: Contribution to journalArticle

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Abstract

This contribution reports a solution and solid-state structural study of the aqueous nucleobase and nucleotide coordination chemistry of the organometallic antineoplastic agent, Cp2MoCl2 (1, Cp = η5-C5H5). In neutral aqueous solution, Cp2MoCl2 undergoes essentially complete chloride aquation within 60 min to yield what is formulated as Cp2Mo(H2O)OH+, while under the same conditions, the Mo-Cp bonds are hydrolytically stable. Reaction of aqueous Cp2MoCl2 with the alkylated nucleobases, 9-methyladenine and 1-methylcytosine yields two isomeric [Cp2Mo(9-methyladenyl)] [PF6] complexes (3a and 3b) and a single isomer of [Cp2Mo(1-methylcytosyl)] [PF6] (4). On the basis of solution NMR spectroscopy, 3a and 3b are assigned HN6-/N1 and HN6-/N7 chelation modes, respectively, while 4 involves an HN4-/N3 chelation mode. Complex 3a crystallizes in the triclinic space group P1̄ with a = 10.682 (3) Å, b = 11.619 (5) Å, c = 7.701 (5) Å, α = 106.93 (4)°, β = 96.32 (3)°, γ = 86.98 (3)°, V = 908.64 Å3, Z = 2; R(F) = 0.045 for 3614 independent reflections having 1 > 3σ(I). The Cp2Mo2+ fragment is in a bent sandwich geometry with an average Mo-C distance of 2.309 (4) Å, a Mo-N1 distance of 2.173 (3) Å, a Mo-N6 distance of 2.145 (3) Å, a N1-Mo-N6 angle of 60.9 (1)°, and a ring centroid-Mo-ring centroid angle of 135.3°. The 9-methyladenyl ligand in 3a lies in the plane which bisects the ring centroid-Mo-ring centroid angle. Chelation constricts the N6-C6-N1 angle to 108.5 (3)°. Complex 4 crystallizes in the monoclinic space group (P21/c) with a = 11.703 (1) Å, b = 10.794 (2) Å, c = 14.416 (2) Å, β = 111.28 (1)°, Z = 4, V = 1696.8 Å13; R(F) = 0.047 for 3007 independent reflections having 1 > 3σ(I). The Cp1Mo2+ fragment is also in a bent sandwich geometry with an average Mo-C distance of 2.294 (7) Å, a MO-N4 distance of 2.140 (5) Å, a Mo-N3 distance of 2.130 (5) Å, a N1-Mo-N6 angle of 59.9 (1)°, and a ring centroid-Mo-ring centroid angle of 136.5°. The 1-methylcytosyl ligand in 4 lies in the plane which bisects the ring centroid-Mo-ring centroid angle, and chelation constricts the N4-C4-N3 angle to 106.8 (5)°. On the NMR time scale and in the absence of other competing ligands, complex 1 forms 1:1 complexes with the 2′-deoxyribonucleotide-5′-monophosphates of guanosine (5′-dGMP), adenosine (5′-dAMP), cytosine (5′-dCMP), and thymidine (5′-dTMP). There is little selectivity in the complexation, and nucleotide-nucleotide exchange processes are detectable. Although nucleotide complexation is observed, there is no NMR evidence that Cp2MoCl2(aq) disrupts Watson-Crick base pairing in 5′-dGMP/5′-dCMP or 5′-dAMP/5′-dTMP dimers. The Cp2Mo2+ adduct of 5′-dGMP (5) crystallizes in the triclinic space group P1 with a = 10.690 (3) Å, b = 14.567 (5) Å, c = 9.298 (3) Å, α = 107.20 (2)°, β = 99.22 (3)°, γ = 77.62 (3)°, Z = l, V = 1344 (2) Å3; R(F) = 0.045 for 5491 independent reflections having I > 3σ(I). The crystal structure of complex 5 consists of dimeric [Cp2Mo(5′-dGMP)]2 units interconnected by water bridges. Each Cp2Mo2 unit of the dimer is in a bent sandwich geometry and is coordinated to N7 and O(phosphate) of different 5′-dGMP moieties. Metrical parameters for 5 are as follows: Mo-C distance(av), 2.307 (9) Å; Mo-N7 distance, 2.20 (1) Å; Mo-O(phosphate) distance, 2.096 (9) Å; N7-Mo-O(phosphate) angle, 77.8 (2)°; and ring centroid-Mo-ring centroid angle, 133.8 (6)°. The 5′-dGMP unit has βgg and γgt torsional conformers and exhibits an unusual syn glycosidic and C3′-endo sugar puckering conformation. Compound 1 forms a monomeric complex with 5′-dAMP (6) in aqueous solution via Mo-N7 and Mo-O(phosphate) chelation, two complexes with 5′-dCMP that both involve O(phosphate) coordination, and a single complex with 5′-dTMP which involves O(phosphate) and N3 coordination. These results place significant ligational restrictions on the mode(s) by which Cp2MX2(aq) species might bind to DNA and, together with a molecular graphics investigation of Cp2Mo+2 coordination to a model oligonucleotide duplex, argue against cisplatinlike complexation motifs.

Original languageEnglish
Pages (from-to)9027-9045
Number of pages19
JournalJournal of the American Chemical Society
Volume113
Issue number24
Publication statusPublished - 1991

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Antineoplastic Agents
Chelation
Phosphates
DNA
Nucleotides
Complexation
Guanosine Monophosphate
Ligands
Dimers
Geometry
Molecular graphics
Nuclear magnetic resonance
Deoxyribonucleotides
Oligonucleotides
Cytosine
Organometallics
Sugars
Base Pairing
Isomers
Adenosine

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Metallocene antitumor agents. Solution and solid-state molybdenocene coordination chemistry of DNA constituents. / Kuo, Louis Y.; Kanatzidis, Mercouri G; Sabat, Michal; Tipton, Andrew L.; Marks, Tobin J.

In: Journal of the American Chemical Society, Vol. 113, No. 24, 1991, p. 9027-9045.

Research output: Contribution to journalArticle

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title = "Metallocene antitumor agents. Solution and solid-state molybdenocene coordination chemistry of DNA constituents",
abstract = "This contribution reports a solution and solid-state structural study of the aqueous nucleobase and nucleotide coordination chemistry of the organometallic antineoplastic agent, Cp2MoCl2 (1, Cp = η5-C5H5). In neutral aqueous solution, Cp2MoCl2 undergoes essentially complete chloride aquation within 60 min to yield what is formulated as Cp2Mo(H2O)OH+, while under the same conditions, the Mo-Cp bonds are hydrolytically stable. Reaction of aqueous Cp2MoCl2 with the alkylated nucleobases, 9-methyladenine and 1-methylcytosine yields two isomeric [Cp2Mo(9-methyladenyl)] [PF6] complexes (3a and 3b) and a single isomer of [Cp2Mo(1-methylcytosyl)] [PF6] (4). On the basis of solution NMR spectroscopy, 3a and 3b are assigned HN6-/N1 and HN6-/N7 chelation modes, respectively, while 4 involves an HN4-/N3 chelation mode. Complex 3a crystallizes in the triclinic space group P1̄ with a = 10.682 (3) {\AA}, b = 11.619 (5) {\AA}, c = 7.701 (5) {\AA}, α = 106.93 (4)°, β = 96.32 (3)°, γ = 86.98 (3)°, V = 908.64 {\AA}3, Z = 2; R(F) = 0.045 for 3614 independent reflections having 1 > 3σ(I). The Cp2Mo2+ fragment is in a bent sandwich geometry with an average Mo-C distance of 2.309 (4) {\AA}, a Mo-N1 distance of 2.173 (3) {\AA}, a Mo-N6 distance of 2.145 (3) {\AA}, a N1-Mo-N6 angle of 60.9 (1)°, and a ring centroid-Mo-ring centroid angle of 135.3°. The 9-methyladenyl ligand in 3a lies in the plane which bisects the ring centroid-Mo-ring centroid angle. Chelation constricts the N6-C6-N1 angle to 108.5 (3)°. Complex 4 crystallizes in the monoclinic space group (P21/c) with a = 11.703 (1) {\AA}, b = 10.794 (2) {\AA}, c = 14.416 (2) {\AA}, β = 111.28 (1)°, Z = 4, V = 1696.8 {\AA}13; R(F) = 0.047 for 3007 independent reflections having 1 > 3σ(I). The Cp1Mo2+ fragment is also in a bent sandwich geometry with an average Mo-C distance of 2.294 (7) {\AA}, a MO-N4 distance of 2.140 (5) {\AA}, a Mo-N3 distance of 2.130 (5) {\AA}, a N1-Mo-N6 angle of 59.9 (1)°, and a ring centroid-Mo-ring centroid angle of 136.5°. The 1-methylcytosyl ligand in 4 lies in the plane which bisects the ring centroid-Mo-ring centroid angle, and chelation constricts the N4-C4-N3 angle to 106.8 (5)°. On the NMR time scale and in the absence of other competing ligands, complex 1 forms 1:1 complexes with the 2′-deoxyribonucleotide-5′-monophosphates of guanosine (5′-dGMP), adenosine (5′-dAMP), cytosine (5′-dCMP), and thymidine (5′-dTMP). There is little selectivity in the complexation, and nucleotide-nucleotide exchange processes are detectable. Although nucleotide complexation is observed, there is no NMR evidence that Cp2MoCl2(aq) disrupts Watson-Crick base pairing in 5′-dGMP/5′-dCMP or 5′-dAMP/5′-dTMP dimers. The Cp2Mo2+ adduct of 5′-dGMP (5) crystallizes in the triclinic space group P1 with a = 10.690 (3) {\AA}, b = 14.567 (5) {\AA}, c = 9.298 (3) {\AA}, α = 107.20 (2)°, β = 99.22 (3)°, γ = 77.62 (3)°, Z = l, V = 1344 (2) {\AA}3; R(F) = 0.045 for 5491 independent reflections having I > 3σ(I). The crystal structure of complex 5 consists of dimeric [Cp2Mo(5′-dGMP)]2 units interconnected by water bridges. Each Cp2Mo2 unit of the dimer is in a bent sandwich geometry and is coordinated to N7 and O(phosphate) of different 5′-dGMP moieties. Metrical parameters for 5 are as follows: Mo-C distance(av), 2.307 (9) {\AA}; Mo-N7 distance, 2.20 (1) {\AA}; Mo-O(phosphate) distance, 2.096 (9) {\AA}; N7-Mo-O(phosphate) angle, 77.8 (2)°; and ring centroid-Mo-ring centroid angle, 133.8 (6)°. The 5′-dGMP unit has βgg and γgt torsional conformers and exhibits an unusual syn glycosidic and C3′-endo sugar puckering conformation. Compound 1 forms a monomeric complex with 5′-dAMP (6) in aqueous solution via Mo-N7 and Mo-O(phosphate) chelation, two complexes with 5′-dCMP that both involve O(phosphate) coordination, and a single complex with 5′-dTMP which involves O(phosphate) and N3 coordination. These results place significant ligational restrictions on the mode(s) by which Cp2MX2(aq) species might bind to DNA and, together with a molecular graphics investigation of Cp2Mo+2 coordination to a model oligonucleotide duplex, argue against cisplatinlike complexation motifs.",
author = "Kuo, {Louis Y.} and Kanatzidis, {Mercouri G} and Michal Sabat and Tipton, {Andrew L.} and Marks, {Tobin J}",
year = "1991",
language = "English",
volume = "113",
pages = "9027--9045",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "24",

}

TY - JOUR

T1 - Metallocene antitumor agents. Solution and solid-state molybdenocene coordination chemistry of DNA constituents

AU - Kuo, Louis Y.

AU - Kanatzidis, Mercouri G

AU - Sabat, Michal

AU - Tipton, Andrew L.

AU - Marks, Tobin J

PY - 1991

Y1 - 1991

N2 - This contribution reports a solution and solid-state structural study of the aqueous nucleobase and nucleotide coordination chemistry of the organometallic antineoplastic agent, Cp2MoCl2 (1, Cp = η5-C5H5). In neutral aqueous solution, Cp2MoCl2 undergoes essentially complete chloride aquation within 60 min to yield what is formulated as Cp2Mo(H2O)OH+, while under the same conditions, the Mo-Cp bonds are hydrolytically stable. Reaction of aqueous Cp2MoCl2 with the alkylated nucleobases, 9-methyladenine and 1-methylcytosine yields two isomeric [Cp2Mo(9-methyladenyl)] [PF6] complexes (3a and 3b) and a single isomer of [Cp2Mo(1-methylcytosyl)] [PF6] (4). On the basis of solution NMR spectroscopy, 3a and 3b are assigned HN6-/N1 and HN6-/N7 chelation modes, respectively, while 4 involves an HN4-/N3 chelation mode. Complex 3a crystallizes in the triclinic space group P1̄ with a = 10.682 (3) Å, b = 11.619 (5) Å, c = 7.701 (5) Å, α = 106.93 (4)°, β = 96.32 (3)°, γ = 86.98 (3)°, V = 908.64 Å3, Z = 2; R(F) = 0.045 for 3614 independent reflections having 1 > 3σ(I). The Cp2Mo2+ fragment is in a bent sandwich geometry with an average Mo-C distance of 2.309 (4) Å, a Mo-N1 distance of 2.173 (3) Å, a Mo-N6 distance of 2.145 (3) Å, a N1-Mo-N6 angle of 60.9 (1)°, and a ring centroid-Mo-ring centroid angle of 135.3°. The 9-methyladenyl ligand in 3a lies in the plane which bisects the ring centroid-Mo-ring centroid angle. Chelation constricts the N6-C6-N1 angle to 108.5 (3)°. Complex 4 crystallizes in the monoclinic space group (P21/c) with a = 11.703 (1) Å, b = 10.794 (2) Å, c = 14.416 (2) Å, β = 111.28 (1)°, Z = 4, V = 1696.8 Å13; R(F) = 0.047 for 3007 independent reflections having 1 > 3σ(I). The Cp1Mo2+ fragment is also in a bent sandwich geometry with an average Mo-C distance of 2.294 (7) Å, a MO-N4 distance of 2.140 (5) Å, a Mo-N3 distance of 2.130 (5) Å, a N1-Mo-N6 angle of 59.9 (1)°, and a ring centroid-Mo-ring centroid angle of 136.5°. The 1-methylcytosyl ligand in 4 lies in the plane which bisects the ring centroid-Mo-ring centroid angle, and chelation constricts the N4-C4-N3 angle to 106.8 (5)°. On the NMR time scale and in the absence of other competing ligands, complex 1 forms 1:1 complexes with the 2′-deoxyribonucleotide-5′-monophosphates of guanosine (5′-dGMP), adenosine (5′-dAMP), cytosine (5′-dCMP), and thymidine (5′-dTMP). There is little selectivity in the complexation, and nucleotide-nucleotide exchange processes are detectable. Although nucleotide complexation is observed, there is no NMR evidence that Cp2MoCl2(aq) disrupts Watson-Crick base pairing in 5′-dGMP/5′-dCMP or 5′-dAMP/5′-dTMP dimers. The Cp2Mo2+ adduct of 5′-dGMP (5) crystallizes in the triclinic space group P1 with a = 10.690 (3) Å, b = 14.567 (5) Å, c = 9.298 (3) Å, α = 107.20 (2)°, β = 99.22 (3)°, γ = 77.62 (3)°, Z = l, V = 1344 (2) Å3; R(F) = 0.045 for 5491 independent reflections having I > 3σ(I). The crystal structure of complex 5 consists of dimeric [Cp2Mo(5′-dGMP)]2 units interconnected by water bridges. Each Cp2Mo2 unit of the dimer is in a bent sandwich geometry and is coordinated to N7 and O(phosphate) of different 5′-dGMP moieties. Metrical parameters for 5 are as follows: Mo-C distance(av), 2.307 (9) Å; Mo-N7 distance, 2.20 (1) Å; Mo-O(phosphate) distance, 2.096 (9) Å; N7-Mo-O(phosphate) angle, 77.8 (2)°; and ring centroid-Mo-ring centroid angle, 133.8 (6)°. The 5′-dGMP unit has βgg and γgt torsional conformers and exhibits an unusual syn glycosidic and C3′-endo sugar puckering conformation. Compound 1 forms a monomeric complex with 5′-dAMP (6) in aqueous solution via Mo-N7 and Mo-O(phosphate) chelation, two complexes with 5′-dCMP that both involve O(phosphate) coordination, and a single complex with 5′-dTMP which involves O(phosphate) and N3 coordination. These results place significant ligational restrictions on the mode(s) by which Cp2MX2(aq) species might bind to DNA and, together with a molecular graphics investigation of Cp2Mo+2 coordination to a model oligonucleotide duplex, argue against cisplatinlike complexation motifs.

AB - This contribution reports a solution and solid-state structural study of the aqueous nucleobase and nucleotide coordination chemistry of the organometallic antineoplastic agent, Cp2MoCl2 (1, Cp = η5-C5H5). In neutral aqueous solution, Cp2MoCl2 undergoes essentially complete chloride aquation within 60 min to yield what is formulated as Cp2Mo(H2O)OH+, while under the same conditions, the Mo-Cp bonds are hydrolytically stable. Reaction of aqueous Cp2MoCl2 with the alkylated nucleobases, 9-methyladenine and 1-methylcytosine yields two isomeric [Cp2Mo(9-methyladenyl)] [PF6] complexes (3a and 3b) and a single isomer of [Cp2Mo(1-methylcytosyl)] [PF6] (4). On the basis of solution NMR spectroscopy, 3a and 3b are assigned HN6-/N1 and HN6-/N7 chelation modes, respectively, while 4 involves an HN4-/N3 chelation mode. Complex 3a crystallizes in the triclinic space group P1̄ with a = 10.682 (3) Å, b = 11.619 (5) Å, c = 7.701 (5) Å, α = 106.93 (4)°, β = 96.32 (3)°, γ = 86.98 (3)°, V = 908.64 Å3, Z = 2; R(F) = 0.045 for 3614 independent reflections having 1 > 3σ(I). The Cp2Mo2+ fragment is in a bent sandwich geometry with an average Mo-C distance of 2.309 (4) Å, a Mo-N1 distance of 2.173 (3) Å, a Mo-N6 distance of 2.145 (3) Å, a N1-Mo-N6 angle of 60.9 (1)°, and a ring centroid-Mo-ring centroid angle of 135.3°. The 9-methyladenyl ligand in 3a lies in the plane which bisects the ring centroid-Mo-ring centroid angle. Chelation constricts the N6-C6-N1 angle to 108.5 (3)°. Complex 4 crystallizes in the monoclinic space group (P21/c) with a = 11.703 (1) Å, b = 10.794 (2) Å, c = 14.416 (2) Å, β = 111.28 (1)°, Z = 4, V = 1696.8 Å13; R(F) = 0.047 for 3007 independent reflections having 1 > 3σ(I). The Cp1Mo2+ fragment is also in a bent sandwich geometry with an average Mo-C distance of 2.294 (7) Å, a MO-N4 distance of 2.140 (5) Å, a Mo-N3 distance of 2.130 (5) Å, a N1-Mo-N6 angle of 59.9 (1)°, and a ring centroid-Mo-ring centroid angle of 136.5°. The 1-methylcytosyl ligand in 4 lies in the plane which bisects the ring centroid-Mo-ring centroid angle, and chelation constricts the N4-C4-N3 angle to 106.8 (5)°. On the NMR time scale and in the absence of other competing ligands, complex 1 forms 1:1 complexes with the 2′-deoxyribonucleotide-5′-monophosphates of guanosine (5′-dGMP), adenosine (5′-dAMP), cytosine (5′-dCMP), and thymidine (5′-dTMP). There is little selectivity in the complexation, and nucleotide-nucleotide exchange processes are detectable. Although nucleotide complexation is observed, there is no NMR evidence that Cp2MoCl2(aq) disrupts Watson-Crick base pairing in 5′-dGMP/5′-dCMP or 5′-dAMP/5′-dTMP dimers. The Cp2Mo2+ adduct of 5′-dGMP (5) crystallizes in the triclinic space group P1 with a = 10.690 (3) Å, b = 14.567 (5) Å, c = 9.298 (3) Å, α = 107.20 (2)°, β = 99.22 (3)°, γ = 77.62 (3)°, Z = l, V = 1344 (2) Å3; R(F) = 0.045 for 5491 independent reflections having I > 3σ(I). The crystal structure of complex 5 consists of dimeric [Cp2Mo(5′-dGMP)]2 units interconnected by water bridges. Each Cp2Mo2 unit of the dimer is in a bent sandwich geometry and is coordinated to N7 and O(phosphate) of different 5′-dGMP moieties. Metrical parameters for 5 are as follows: Mo-C distance(av), 2.307 (9) Å; Mo-N7 distance, 2.20 (1) Å; Mo-O(phosphate) distance, 2.096 (9) Å; N7-Mo-O(phosphate) angle, 77.8 (2)°; and ring centroid-Mo-ring centroid angle, 133.8 (6)°. The 5′-dGMP unit has βgg and γgt torsional conformers and exhibits an unusual syn glycosidic and C3′-endo sugar puckering conformation. Compound 1 forms a monomeric complex with 5′-dAMP (6) in aqueous solution via Mo-N7 and Mo-O(phosphate) chelation, two complexes with 5′-dCMP that both involve O(phosphate) coordination, and a single complex with 5′-dTMP which involves O(phosphate) and N3 coordination. These results place significant ligational restrictions on the mode(s) by which Cp2MX2(aq) species might bind to DNA and, together with a molecular graphics investigation of Cp2Mo+2 coordination to a model oligonucleotide duplex, argue against cisplatinlike complexation motifs.

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M3 - Article

AN - SCOPUS:0026317120

VL - 113

SP - 9027

EP - 9045

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 24

ER -