Limits...
Synthesis, anti-tubulin and antiproliferative SAR of steroidomimetic dihydroisoquinolinones.

Leese MP, Jourdan FL, Major MR, Dohle W, Thomas MP, Hamel E, Ferrandis E, Mahon MF, Newman SP, Purohit A, Potter BV - ChemMedChem (2014)

Bottom Line: The carbonyl-linked DHIQs in particular exhibit significant in vitro antiproliferative activities (e.g., 6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydroisoquinolin-1(2H)-one (16 g): GI50 51 nM in DU-145 cells).The broad anticancer activity of DHIQ 16 g was confirmed in the NCI 60-cell line assay giving a mean activity of 33 nM.Additionally, X-ray and computational analyses of 17 f reveal that electrostatic repulsion between the two adjacent carbonyl groups, through conformational biasing, dictates the adoption of a "steroid-like" conformation that may partially explain the excellent in vitro activities.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Bath, BA2 7AY (UK).

Show MeSH

Related in: MedlinePlus

a) Single-crystal X-ray structure of 17 f. Ellipsoids are depicted at 30 % probability. b) Part of the crystal lattice packing diagram of 17 f to illustrate the hydrogen-bonded linear arrangements present in the gross structure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4114533&req=5

fig03: a) Single-crystal X-ray structure of 17 f. Ellipsoids are depicted at 30 % probability. b) Part of the crystal lattice packing diagram of 17 f to illustrate the hydrogen-bonded linear arrangements present in the gross structure.

Mentions: Finally, an X-ray crystal structure of 17 f was obtained to explore conformational effects (Figure 3).[15] The crystal structure shows that in the solid state the molecule adopts a “steroid-like” conformation as planned with a dihedral angle of 148.4° between the two carbonyl groups (Figure 3 a). In the single crystal this fixed angle also appears as a result of positive intermolecular interactions (Figure 3 b). The sulfamate group plays a key role to stabilise the framework of the lattice structure by acting as a hydrogen donor to the C3′-methoxy group of a second molecular unit that is part of the same string and to the carbonyl group at C1 of a third molecular unit that is part of a second string running in the opposite direction. The angles in the crystal structure do not necessarily reflect conditions in solution. However, the excellent in vitro antiproliferative activities obtained for this class of compound suggest that adoptable conformations might be very restricted in solution as well, mainly as a result of electrostatic repulsion between the two carbonyl groups, and somewhere around the angle observed in the crystal. Control compounds like 8 d–e and 9 d–e without the carbonyl group in the linker to the D-ring mimic and 18 b–c and 19 b–c without the carbonyl at C1 do not have this favourable restriction and therefore show far less potency than their counterparts 16 f–g and 17 f–g that have both carbonyl groups present.


Synthesis, anti-tubulin and antiproliferative SAR of steroidomimetic dihydroisoquinolinones.

Leese MP, Jourdan FL, Major MR, Dohle W, Thomas MP, Hamel E, Ferrandis E, Mahon MF, Newman SP, Purohit A, Potter BV - ChemMedChem (2014)

a) Single-crystal X-ray structure of 17 f. Ellipsoids are depicted at 30 % probability. b) Part of the crystal lattice packing diagram of 17 f to illustrate the hydrogen-bonded linear arrangements present in the gross structure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4114533&req=5

fig03: a) Single-crystal X-ray structure of 17 f. Ellipsoids are depicted at 30 % probability. b) Part of the crystal lattice packing diagram of 17 f to illustrate the hydrogen-bonded linear arrangements present in the gross structure.
Mentions: Finally, an X-ray crystal structure of 17 f was obtained to explore conformational effects (Figure 3).[15] The crystal structure shows that in the solid state the molecule adopts a “steroid-like” conformation as planned with a dihedral angle of 148.4° between the two carbonyl groups (Figure 3 a). In the single crystal this fixed angle also appears as a result of positive intermolecular interactions (Figure 3 b). The sulfamate group plays a key role to stabilise the framework of the lattice structure by acting as a hydrogen donor to the C3′-methoxy group of a second molecular unit that is part of the same string and to the carbonyl group at C1 of a third molecular unit that is part of a second string running in the opposite direction. The angles in the crystal structure do not necessarily reflect conditions in solution. However, the excellent in vitro antiproliferative activities obtained for this class of compound suggest that adoptable conformations might be very restricted in solution as well, mainly as a result of electrostatic repulsion between the two carbonyl groups, and somewhere around the angle observed in the crystal. Control compounds like 8 d–e and 9 d–e without the carbonyl group in the linker to the D-ring mimic and 18 b–c and 19 b–c without the carbonyl at C1 do not have this favourable restriction and therefore show far less potency than their counterparts 16 f–g and 17 f–g that have both carbonyl groups present.

Bottom Line: The carbonyl-linked DHIQs in particular exhibit significant in vitro antiproliferative activities (e.g., 6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydroisoquinolin-1(2H)-one (16 g): GI50 51 nM in DU-145 cells).The broad anticancer activity of DHIQ 16 g was confirmed in the NCI 60-cell line assay giving a mean activity of 33 nM.Additionally, X-ray and computational analyses of 17 f reveal that electrostatic repulsion between the two adjacent carbonyl groups, through conformational biasing, dictates the adoption of a "steroid-like" conformation that may partially explain the excellent in vitro activities.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Bath, BA2 7AY (UK).

Show MeSH
Related in: MedlinePlus