Xianghong Huang

Synthesis of Anti‐Microtubule N‐(2‐Arylindol‐7‐yl)benzenesulfonamide Derivatives and Their Antitumor Mechanisms

Prostate cancer is one of the most common cancers in men worldwide, and its incidence has increased even in the last few years. Clinically, patients with prostate cancer initially respond effectively to androgen depletion therapy, which induces apoptosis of tumor cells. However, androgen depletion therapy becomes ineffective in most patients after a period of time. In these hormone-refractory prostate cancer cases, tumors become metastatic and patient mortality is high. As apoptosis-resistant prostate cancer is resistant to conventional chemotherapeutic drugs, it is necessary to develop novel agents for the treatment of HRPC. Microtubules are a promising target for anticancer drug development. Anti-microtubule drugs perturb the dynamics of microtubules, and consequently arrest cell cycle progression and induce apoptosis. Clinically, anti-microtubule drugs have shown potent activity in the treatment of patients with HRPC. 7] Development of a new generation of antimicrotubule drugs is still ongoing, with the goal of improving efficacy and safety. 9] Combretastatin A4 and its derivatives not only show excellent antitumor efficacy but also exhibit antiangiogenesis activity. N-{2-[(4-Hydroxyphenyl)amino]-3-pyridinyl}-4-methoxybenzenesulfonamide (I, E7010, also called ABT-571) and its analogues (Figure 1) are demonstrated to have potent antitumor activity against drug-resistant tumor cell lines both in vitro and in vivo. E7010 binds to the colchicine binding site of tubulin and consequently inhibits tubulin polymerization, and blocks mitosis. 19] Ring connection of E7010 yields N-(2-chloroindol-7-yl)-4-methoxybenzenesulfonamide (II), which retains antimitotic activity. However, structure–activity relationship studies have demonstrated that structural alterations result in different antitumor mechanisms. N-(3-Chloroindol-7-yl)-1,4-benzenedisulfonamide (IV, E7070) induces cell-cycle arrest at the G1 and/or G2 phase. [11, 13] Alteration of the 2-chloroindole derivative II results in the corresponding 3-chloroindole derivative III. Interestingly, compound III exhibits the dual functions of II and IV. Both substitutions on the C4 position of benzenesulfonamide and on the indole ring affect antitumor mechanisms. Herein we report a series of N-(2-arylindol-7-yl)benzenesulfonamide derivatives and the antitumor mechanism of the most potent compound, N-(2-phenylindol-7-yl)-4-methoxybenzenesulfonamide (2).

Crystal structures of p-methyl-N-(2-phenyl-1H-indol-7-yl)-benzene-sulfonamide, C21H18N2O2S, and p-methoxy-N-(2-phenyl-1H-indol-7-yl)-benzene-sulfonamide,C21H18N2O3S

C21H18N2O2S, orthorhombic, Pbca (no. 61), a = 5.030(1) A, b = 18.894(4) A, c = 36.178(7) A, V= 3438.2 A 3 ,Z= 8, Rgt(F) = 0.052, wRntfF) = 0.120, Γ= 100 K. C21H18N2O3S, orthorhombic, Pbca (no. 61), a = 5.018(2) A, b = 20.010(7) A, c = 35.34(1) A, V = 3548.5 A, Ζ = 8, RfffF) = 0.056, wRkJF) = 0.137, T= 100 K. Source of material Basic 2-phenyl-indole group was prepared from selectively protected 2-amino-3-nitrophenol and phenylacetylene, according to Sonogashira coupling reaction [1]. The resulting 7-nitro-2-phenylindole was reduced into 7-amino-2-phenyindole with hydrogen by Pd/C and then converted into p-substituted N-(2-phenyl-l//indol-7-yl)-benzene-sulfonamides with the corresponding p-substituted benzene-sulfonyl chloride in pyridine and tetrahydrofuran [2]. Colorless single crystals for X-ray analysis were grown by slow evaporation of the solutions of the compounds in ethyl acetate at 4 °C. * Correspondence author (e-mail: zhangqf@ahut.edu.cn) Discussion Individual syntheses of new heterocycles from indole have attached the attention of chemists in recent years because of their extensive application in biological activity [3]. An active intermediate N-( 1 //-indol-7-yl)methanesulfonamide is reacted with the appropriate carbinol to give the indole-derived modulators for the steroid hormone nuclear receptors [4]; the typical 2-arylidene-3-indolinone compounds obtained from direct hydrolysis of the a primary or secondary aryl amines are effective components for oxidative hair dyes [5]; the N-(7-indolyl)benzene-sulfonamides as a potential antitumor agent have been used for the discovery of potent cell cycle inhibitors [6]. During the design of high-affinity antipsychotic drugs from indole derivatives with amine, the structure-activity relationships of the substituent patterns on the pharmacophore template have been also attended [6]. We determined a series of crystal structures of p-substituted N-(2phenyl-1 //-indol-7-yl)-benzene-sulfonamides by X-ray singlecrystal diffraction to gain better insight into the structures of these molecules with hydrogen-bonding patterns. In the five-membered rings, the angles at N2 atoms are 110.1(3)° for p-methyl-AK2-phenyl-1 ff-indol-7-yl)-benzene-sulfonamide (I), 109.5(3)° for p-methyl-/V-(2-phenyl-1 //-indol-7-yl)-benzenesulfonamide (Π), and 108.7(2)° for p-bromo-A/-(2-phenyl-1Hindol-7-yl)-benzene-sulfonamide (ΠΓ) [7]; the N2—C5 and N2—C8 bond lengths of these compounds [average 1.377(4) A] are well within the range of the values normally considered standard for single C—Ν (1.47 A) and double C=N (1.28 A) bonds, which indicates that the environment around N2 atom is a normal sp-coordination as expected for π-conjugation of the indole ring [7], The indole groups of three compounds are nearly coplanar with the average deviation of 0.0015 A from the least squares plane. The rings of C15 C20 benzene and the planes of the indole groups make dihedral angles of 44.7(3)°, 39.5(3)°, and 40.0(3) for I, Π, and ΙΠ, respectively; while the dihedral angles of the C9 C14 phenyl rings and the indole planes [4.5(2)°forI, 14.5(2)° for Π and 34.9(2)° for ΠΙ] among the three compounds have large differences, suggestive of steric repulsions between the phenyl rings and the indole planes being obviously influenced by different substitute groups. The average N1—C4 and N1—SI bond lengths of the compounds are 1.440(2) A and 1.628(2) A, respectively, indicative of the standard single bond of the .^-hybridized amine-Nl atom. The angles at N1 in the structures of the three compounds are in the range of 117.9(2)° 120.4(2)°. The environment around SI is a highly distorted tetrahedron, indicated by the bond angles of 01-S1-02 [average 120.3(2)°] being largely deviated from the standard planar angle of 109.2°. The average double S = 0 bond length is 1.428(2) A. C21H18N202S, C21H18N203S 259 In the crystal structure of I, two molecules are connected parallel to each other by N H O hydrogen bonds, with an Ν -O distance of 2.963(3) Ä and an N H O angle of 169.1(3)°, to form a onedimensional linear structure. The crystal packing in Π is governed by two kinds of hydrogen bonds: the relatively strong N H O interaction [d (N-0 ) = 2.969(3) A, Z.N-H O = 161.4(3)°] arranging the molecules in chains running along [100] and the relatively weak C-H Ο interaction [d(CO) = 3.251(3) A, Z.C-H-O = 167.4(2)°] connecting the chains into layers parallel to the (001) plane. There is no evidence of any aromatic π-π stacking of the indole rings in the present compounds. In the structure of ΙΠ, a pair of head-to-tail intermolecular N-H -O bonds link adjacent molecules to form a dimer which is farther linked via the N-H -O bonds [rf(N -O) = 2.873(3) Α, Z. N H O = 166.6(3)] to form a one-dimensional column [8]. 1. /7-Methyl-A-(2-phenyI-li/-indol-7-yl)-benzene-sulfon-

2-(2,2,2-Trifluoroacetylamino)pyridin-3-yl trifluoromethanesulfonate

The synthesis of aza-7-indoles, which are the starting reagents for the synthesis of pharmacologically active compounds having an indole nucleus (MeÂrour & Joseph, 2001), requires the title compound, 2-tri ̄uoroacetoamino-3-pyridine trīuoromethanesulfonate (I), in one of the steps. The asymmetric unit of the title compound consists of two independent molecules that are linked by a pair of Namido Npyridyl hydrogen bonds [2.858 (2) and 2.880 (2) AÊ ] into a dimeric entity (see Fig. 1 and Table 2). In the two molecules, the conformation of the tri ̄uoroacetylamino group is almost the same but the conformation of the tri ̄uoromethanesulfonate group is different (see the torsion angles in Table 1).

2‐(2,2,2‐Tri­fluoro­acetyl­amino)­pyridin‐3‐yl tri­fluoro­methane­sulfonate. Addendum

Owing to unfortunate circumstances the paper by Huang, Zhang & Sung [Acta Cryst. (2004), E60, o708–o710] reports the same structure as the paper by Huang, Liu, Hu & Ng [Acta Cryst. (2004), E60, o308–o309] and hence the two papers should be read together. The authors of the later paper apologise unreservedly for this problem.