Nucleic acids and constituents. XXVII. Crystal structure of 5'-methylene adenosine 3',5'-cyclic monophosphonate monohydrate, biologically active analog of the secondary hormonal messenger cyclic adenosine 3',5'-monophosphate. Conformational rigidity furanose ring in cyclic nucleotides

Sundaralingam, M.; Abola, J.

doi:10.1021/ja00769a047

Cited by 40 publications

(19 citation statements)

References 5 publications

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“…As in the other cyclic nucleotide structures (18)(19)(20)(21)(22)(23), the conformation about the C4'-C5' bond is fixed as trans-gauche. The six-membered phosphodiester ring is in a distorted chair conformation with the largest degree of pucker occurring at the C3'-C4' inter-ring junction.…”

Section: Results Biologicalmentioning

confidence: 71%

“…The six-membered phosphodiester ring is in a distorted chair conformation with the largest degree of pucker occurring at the C3'-C4' inter-ring junction. The P-O-ethyl group is axial, as is the comparable oxygen in the other cyclic nucleotide structures (18)(19)(20)(21)(22)(23). In Et-cAMP this ring is somewhat more flattened than that seen in the other cyclic nucleotides.…”

Section: Results Biologicalmentioning

confidence: 85%

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Tumor-inhibiting properties of the neutral P-O-ethyl ester of adenosine 3':5'-monophosphate in correlation with its crystal and molecular structure.

Cotton¹,

Gillen²,

Gohil³

et al. 1975

Proc. Natl. Acad. Sci. U.S.A.

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The P-O-ethyl ester of cAMP has been synthesized, its inhibition of solid and ascites tumors studied, and its pattern of urinary excretion followed. Et-cAMP is more effective than cAMP against solid sarcoma The recognition that altered cAMP levels may be an important biochemical lesion underlying diverse human diseases (1) has opened new avenues of rational drug design (2). Of the great variety of cAMP derivatives and analogs reported over the years (3), phosphotriesters of cAMP (4) offer the combined advantage of metabolic stability and cell penetration. This rationale led Nagyvary et al. (4) to the synthesis of several protected and unprotected (5) cAMP P-O-alkyl esters. The N6-diacetyl derivatives of Me-cAMP and Et-cAMP were found active on Ehrlich ascites carcinoma both in vivo and in vitro (4). It was proposed that the biological activity of these triesters could be linked to their functioning as storage forms of cAMP, which is known to inhibit tumors (6).In the chemical synthesis (4), cAMP was reacted with triisopropyl benzenesulfonyl chloride and the resulting mixed anhydride was subjected to alcoholysis. Although a transesterification leading to a neutral cAMP phosphoamidate was reported to be highly stereoselective for the exo form (7), two diastereomers are possible here. Thus, to establish the exact structure of the biologically active P-O-ethyl ester of cAMP studied in this work, its crystal structure was determined. This paper reports the results of this determination as well as some evidence of the superiority of this neutral ester to exogenous cAMP as a biologically active agent. MATERIALS AND METHODSCrystallography. Precession photographs of a needle-shaped crystal, 0.4 X 0.04 X 0.04 mm, established that the crystal belonged to the monoclinic space groups P21 (C22) or P21/ m(C2h2). The latter would be inconsistent with the chirality of the molecules and was also disfavored by the statistical distribution of the normalized structure factors. All further measurements were made on a Syntex P1 diffractometer utilizing incident beam monochromatized Mo Ka radiation.Fifteen medium-angle reflections gave refined unit cell dimensions of a = 10.340 (7) A, b = 6.851(4) A, c = 12.464 (7) A, , = 65.95(5)0 and V = 806.2(8) A'. The inclusion of the two water molecules found in the unit cell during refinement yields a calculated density of 1.54 g cm'-for Z = 2. The 1554 independent reflections to a 20 maximum of 500 were collected by standard 0-20 scan techniques. No degradation of standard reflections was observed. Lorenz and polarization corrections were applied, but no absorption correction was made (MA = 2.3 cm-'). Only those 708 reflections for which F02 > 3o-(Fo2) were employed to solve and refine the structure; attempts to include additional reflections to F02 > 1.5a (Fo2) led to unreasonable values for bond distances and angles.The structure was solved using the MULTAN programs

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Section: Results Biologicalmentioning

confidence: 71%

Section: Results Biologicalmentioning

confidence: 85%

Tumor-inhibiting properties of the neutral P-O-ethyl ester of adenosine 3':5'-monophosphate in correlation with its crystal and molecular structure.

Cotton¹,

Gillen²,

Gohil³

et al. 1975

Proc. Natl. Acad. Sci. U.S.A.

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“…There are five different hydrogen bonds (Table 4), the strongest [2.521 (3)/k] is between the protonated N(7) atom and a phosphate O atom of an adjacent molecule. In the zwitterionic 5'-methyleneadenosine cyclic 3',5'-monophosphonate (Sundaralingam & Abola, 1972), a somewhat longer hydrogen bond (2.651 ,/~) was observed between the negatively charged phosphonate 0(6) and the positively charged base N(1) site. Three of the five hydrogen bonds in the structure involve the water of crystallization which forms a hydrogen-bonded bridge between the 2'-hydroxyl group of the ribose and the base N(3) atom of the same molecule, while donating its other H atom to a phosphate O atom of a screw-related molecule.…”

Section: Hydrogen Bonding and Molecular Packingmentioning

confidence: 98%

“…The last column reports standard deviations from the mean of the tabulated values. *Compound names and references: (1) 5'-Methyleneadenosine cyclic 3',5'-monophosphonate monohydrate [C(6')=O(5')], Sundaralingam & Abola (1972). (2) P-O-Ethyl ester of adenosine cyclic 3',5'-monophosphate, Cotton, Gillen.…”

Section: Table 3 Comparison Of Conformational Parameters For 3'5'-cmentioning

confidence: 99%

The structure of the zwitterion inosine cyclic 3',5'-monophosphate (cIMP) monohydrate. Analysis of torsional flexibility in the furano–phosphate moiety

Sundaralingam¹,

Haromy²,

Prusiner³

1982

Acta Crystallogr Sect B

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Inosine cyclic 3',5'-monophosphate (clMP), which has been implicated in hormonal and regulatory control mechanisms, crystallizes with one water molecule of hydration (C 10HI1NaO7P. H20) in the monoclinic space group P2~ (Z = 2) with unit-cell constants a --6.190 (3), b = 13.090 (2), c = 9.095 (2) A and fl = 108.43 (2)°; do = 1.656, d c = 1.654 g cm -3. The structure was solved by the multisolution technique and refined by the least-squares method to a final R of 0.034 using 1422 intensities. The free acid of clMP, which exists in the zwitterionic form with protonation at N(7) of the base, exhibits the anti conformation: Z = 18.1 (3) °, and the 3T 4 pucker for the ribofuranose ring: P = 27.6 (2) ° and r m = 43.4 (2) °. The phosphate ring is in the chair conformation and exhibits the sharpest pucker at the ribose C(3')-C(4') bond. The anti orientation of the base is stabilized by hydrogen bonds from the water of hydration to the base N(3) site and the ribose 0(2') atom of the same molecule. The protonated base atom N (7) is involved in the strongest hydrogen bond of 2.521 (3)A to a phosphate O atom of an adjacent nucleotide. The conformational variability for the phosphodiester ring, between different 3',5'-cyclic nucleotide structures, increases as one moves from the ribose C-C bonds to the phosphate P-O bonds.

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“…The atomic parameters are given in Tables 1 and 2 (Bugg & Sternglanz, 1974; and references therein) the nucleosides are in the syn conformation (Donohue & Trueblood, 1960; ZCN, the torsion angle defined by atoms O(1')-C(1')-N(9)-C(8) (Sundaralingam, 1969), is -84.6 ° and -76.1 ° for molecules A and B respectively. The torsion angles of the ribose, r o, r~, r_~, r~, and r 4 (Sundaralingam, 1971;Sundaralingam & Abola, 1972) are -7-0, -17.5, 33-9, -39.1 and 28.9 ° for molecule A and 11.7, -29.7, 35.3, -29.7 and ! 1-4 ° for molecule B.…”

Section: F~)z/(m -S)] 1/2 Where M Is the Number Of Reflectionsmentioning

confidence: 98%

Stacking patterns of halogenated purines: crystal structure of 8-bromoinosine

Sternglanz¹,

Thomas²,

Bugg³

1977

Acta Crystallogr Sect B

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Nucleic acids and constituents. XXVII. Crystal structure of 5'-methylene adenosine 3',5'-cyclic monophosphonate monohydrate, biologically active analog of the secondary hormonal messenger cyclic adenosine 3',5'-monophosphate. Conformational rigidity furanose ring in cyclic nucleotides

Cited by 40 publications

References 5 publications

Tumor-inhibiting properties of the neutral P-O-ethyl ester of adenosine 3':5'-monophosphate in correlation with its crystal and molecular structure.

Tumor-inhibiting properties of the neutral P-O-ethyl ester of adenosine 3':5'-monophosphate in correlation with its crystal and molecular structure.

The structure of the zwitterion inosine cyclic 3',5'-monophosphate (cIMP) monohydrate. Analysis of torsional flexibility in the furano–phosphate moiety

Stacking patterns of halogenated purines: crystal structure of 8-bromoinosine

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