Antiproliferative and apoptotic activity of new indazole derivatives as potential anticancer agents.

To develop potent and selective anticancer agents, a series of novel polysubstituted indazoles was synthesized and evaluated for their in vitro antiproliferative and apoptotic activities against two selected human cancer cell lines (A2780 and A549). Several compounds showed an interesting antiproliferative activity, with IC50 values ranging from 0.64 to 17 µM against both cell lines. The most active indazoles were then tested in different pharmacological dilution conditions, adding five new cell lines (A2780, A549, IMR32, MDA-MB-231, and T47D) as targets, confirming their antiproliferative activity. Furthermore, selected compounds were able to trigger apoptosis to a significant extent and to cause, in part, a block of cells in the S phase of the cell cycle, with a concomitant decrease of cells in the G2/M and/or G0/G1 phases and the generation of hypodiploid peaks. However, molecule 7d caused a great increase of cells in G2/M and the appearance of polyploid cells. Altogether, our results suggest a good pharmacological activity for our selected polysubstituted indazoles, which are suggestive of a preferential mechanism of action as cell cycle-specific antimetabolites or as an inhibitor of enzyme activities involved in DNA synthesis, except for 7d, which, on the contrary, seems to have a mechanism involving the microtubule system.

Crystal structure of 3-chloro-1-methyl-5-nitro-1H-indazole.

The mol-ecule of the title compound, C8H6ClN3O2, is built up from fused five- and six-membered rings connected to a chlorine atom and to nitro and methyl groups. The indazole system is essentially planar with the largest deviation from the mean plane being 0.007 (2) Å. No classical hydrogen bonds are observed in the structure. Two mol-ecules form a dimer organised by a symmetry centre via a close contact between a nitro-O atom and the chlorine atom [at 3.066 (2) Šthis is shorter than the sum of their van der Waals radii].

6,6'-Di-nitro-1,1'-(ethane-1,2-di-yl)di(1H-indazole).

The mol-ecule of the title compound, C16H12N6O4, is built up from two fused five- and six-membered rings linked by an ethyl-ene group. The dihedral angle between the planes through the indazole ring systems is 39.74 (5)°. The nitro groups are tilted by 7.2 (2) and 8.5 (2)° with respect to planes of the fused-ring systems. In the crystal, mol-ecules are linked by C-H⋯N and C-H⋯O hydrogen bonds into chains running parallel to the c axis.

Ethyl 3-[7-(N-acetyl-4-meth-oxy-benzene-sulfonamido)-3-chloro-2H-indazol-2-yl]propionate.

In the title compound, C21H22ClN3O6S, the fused five- and six-membered ring rings are almost perpendicular to the planes through the atoms forming the acetyl and the propionic ester groups, as indicated by the dihedral angles of 80.3 (2) and 88.3 (7)°, respectively. The dihedral angle between the indazole system and the 4-meth-oxy-benzene-sulfonyl group is 13.76 (6)°. The carbonyl O atom is split over two positions in a 0.60 (5):0.40 (5) ratio. In the crystal, mol-ecules are linked by C-H⋯O and C-H⋯N inter-actions into a three-dimensional network.

N-(2-Allyl-4-chloro-2H-indazol-5-yl)-4-meth-oxy-benzene-sulfonamide hemi-hydrate.

The fused five- and six-membered rings in the title compound, C17H16ClN3O3S·0.5H2O, are practically coplanar, with the maximum deviation from the mean plane being 0.057 (3) Šfor the C atom bound to the exocyclic N atom. The indazole system makes a dihedral angle of 66.18 (12)° with the plane through the benzene ring, and it is nearly perpendicular to the allyl group, as indicated by the N-N-C-C torsion angle of 79.2 (3)°. In the crystal, the water mol-ecule, lying on a twofold axis, forms O-H⋯N and accepts N-H⋯O hydrogen bonds. Additional C-H⋯O hydrogen bonds contribute to the formation of a chain along the b-axis direction.

2-Allyl-7-nitro-2H-indazole.

The asymmetric unit of the title compound, C10H9N3O2, contains two independent mol-ecules linked by a C-H⋯N hydrogen bond. Each mol-ecule has a similar conformation, being built up from fused five- and six-membered rings, each linked to an ally and nitro group, respectively. The indazole ring system makes dihedral angles of 2.7 (2) and 2.2 (2)°, respectively, with the plane through the nitro group. The allyl group is nearly perpendicular to the indazole system, as indicated by the N-N-C-C torsion angles of -75.3 (2) and -82.2 (2)°, this being the most important difference between the conformations of the two mol-ecules. In the crystal, mol-ecules are linked by C-H⋯O and π-π [inter-centroid distance = 3.6225 (8) Å] inter-actions to form a three-dimensional network.