Arnicolide D: a multi-targeted anticancer sesquiterpene lactone-preclinical efficacy and mechanistic insights.

Arnicolide D, a potent sesquiterpene lactone from Centipeda minima, has emerged as a promising anticancer candidate, demonstrating significant efficacy in inhibiting cancer cell proliferation, inducing apoptosis, and suppressing metastasis across various cancer models. This comprehensive study delves into the molecular underpinnings of Arnicolide D's anticancer actions, emphasizing its impact on key signaling pathways such as PI3K/AKT/mTOR and STAT3, and its role in modulating cell cycle and survival mechanisms. Quantitative data from preclinical studies reveal Arnicolide D's dose-dependent cytotoxicity against cancer cell lines, including nasopharyngeal carcinoma, triple-negative breast cancer, and human colon carcinoma, showcasing its broad-spectrum anticancer potential. Given its multifaceted mechanisms and preclinical efficacy, Arnicolide D warrants further investigation in clinical settings to validate its therapeutic utility against cancer. The evidence presented underscores the need for rigorous pharmacokinetic and toxicological studies to establish safe dosing parameters for future clinical trials.

Dimethyl 2-[2-(2,4,6-tri-chloro-phen-yl)hydrazin-1-yl-idene]butane-dioate.

In the title compound, C12H11Cl3N2O4, the dihedral angle between the aromatic ring and the hydrazine (NH-N=C) grouping is 52.2 (3)°. The butanedioate groups exhibit planar conformations. An intra-molecular N-H⋯O hydrogen bond links the N-H group of the hydrazine to one of the meth-oxy groups of the butane-dioate moiety. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds and π-π inter-actions are also observed [centroid-centroid separation = 3.535 (1) Å].

(2E)-2-{[3-Methyl-5-(2-naphth-yloxy)-1-phenyl-1H-pyrazol-4-yl]methyl-idene}hydrazinecarbothio-amide monohydrate.

In the title compound, C(22)H(19)N(5)OS·H(2)O, the naphthalene ring system and the benzene ring [dihedral angle = 85.19 (8)°] make dihedral angles of 87.02 (9) and 14.41 (10)°, respectively, with the pyrazole ring. The mean plane through the 2-methyl-enehydrazinecarbothio-amide group [C-N-N-C(=S)-N; maximum deviation = 0.022 (1) Å] is slightly twisted from the pyrazole ring [dihedral angle = 5.60 (11)°]. In the crystal, mol-ecules are linked by N-H⋯S, N-H⋯O, O-H⋯S, O-H⋯N and C-H⋯S hydrogen bonds into sheets parallel to the ab plane. π-π inter-actions are also observed [centroid-to-centroid distances = 3.7778 (12) and 3.7010 (12) Å].

2,3-Dibromo-3-(4-chloro-phen-yl)-1-(4-nitro-thio-phen-2-yl)propan-1-one.

The title compound, C(13)H(8)Br(2)ClNO(3)S, exhibits whole-mol-ecule disorder over two orientations in a 0.805 (6):0.195 (6) ratio. The dihedral angles between the thio-phene ring [maximum deviations = 0.017 (4) and 0.033 (9) Šfor the major and minor components, respectively] and the chloro-substituted phenyl ring are 32.1 (5) (major component) and 26.3 (18)° (minor component). In the crystal, C-H⋯Cl and C-H⋯O hydrogen bonds link the mol-ecules into sheets lying parallel to the bc plane. Aromatic π-π stacking inter-actions [centroid-centroid distance = 3.550 (7) Å] are also observed.

3-(1-Benzofuran-2-yl)-1H-1,2,4-triazole-5(4H)-thione monohydrate.

In the title hydrate, C(10)H(7)N(3)OS·H(2)O, the essentially planar benzofuran [maximum deviation = 0.006 (1) Å] and 4,5-dihydro-1H-1,2,4-triazole [maximum deviation = 0.007 (1) Å] rings form a dihedral angle of 11.67 (6)°. In the crystal, O-H⋯N, O-H⋯S, N-H⋯O and N-H⋯S hydrogen bonds link the mol-ecules into sheets lying parallel to the bc plane. Aromatic π-π stacking inter-actions [centroid-centroid distances = 3.5078 (8)-3.6113 (8) Å] are also observed.

4-Bromo-acetyl-3-phenyl-sydnone.

IN THE TITLE COMPOUND (SYSTEMATIC NAME: 4-bromoacetyl-1,2,3-oxadiazol-3-ylium-5-olate), C(10)H(7)BrN(2)O(3), the 1,2,3-oxadiazole ring and bromo-acetyl group are essentially planar [maximum deviation = 0.010 (4) and 0.013 (3) Šrespectively] and form dihedral angles of 59.31 (19) and 67.96 (11)°, respectively, with the phenyl ring. The 1,2,3-oxadiazole ring is twisted slightly from the mean plane of the bromo-acetyl group, forming a dihedral angle of 9.16 (24)°. In the crystal, mol-ecules are linked by pairs of weak C-H⋯O hydrogen bonds into inversion dimers with R(2) (2)(12) ring motifs. The dimers are further connected by weak C-H⋯O hydrogen bonds into an infinite tape parallel to the b axis. In addition, π-π stacking inter-actions [centroid-centroid distance = 3.6569 (19) Å] and short inter-molecular contacts [O⋯O = 2.827 (3) and C⋯C = 3.088 (5) Å] are observed.

(2E)-2-[(3-Methyl-5-phen-oxy-1-phenyl-1H-pyrazol-4-yl)methyl-idene]hydrazinecarbothio-amide.

In the title compound, C(18)H(17)N(5)OS, the mean plane of the pyrazole ring [maximum deviation = 0.0031 (12) Å] forms dihedral angles of 19.6 (4) and 9.3 (5)° with the two disorder components of the N-bound benzene ring (with equal occupancies for the two orientations) and a dihedral angle of 72.58 (8)° with the C-O-bonded benzene ring. The mol-ecule exists in a trans conformation with respect to the N=C bond [1.2792 (19) Å]. The mol-ecular structure features an intra-molecular C-H⋯O hydrogen bond, forming an S(6) ring. In the crystal, N-H⋯N and N-H⋯S hydrogen bonds result in the formation of zigzag layers lying parallel to (10-1).

3-Methyl-4-[2-(4-nitro-phen-yl)hydrazin-1-yl-idene]-5-oxo-4,5-dihydro-1H-pyrazole-1-carbothio-amide.

The asymmetric unit of the title compound, C(11)H(10)N(6)O(3)S, contains two independent mol-ecules, each of which is stabilized by an intra-molecular N-H⋯O hydrogen bond, forming an S(6) ring motif. In one mol-ecule, the pyrazole ring forms a dihedral angle of 10.93 (14)° with the benzene ring. The corresponding dihedral angle in the other mol-ecule is 7.03 (14)°. In the crystal, mol-ecules are linked via pairs of (N,N)-H⋯O bifurcated acceptor bonds which, together with C-H⋯O hydrogen bonds, form sheets parallel to (001).

N'-[1-(4-Chloro-phen-yl)ethyl-idene]-5-methyl-1-(4-nitro-phen-yl)-1H-1,2,3-triazole-4-carbohydrazide.

In the title compound, C(18)H(15)ClN(6)O(3), the 1,2,3-triazole ring forms dihedral angles of 15.64 (5) and 57.50 (5)° with the two benzene rings. The dihedral angle between the two benzene rings is 72.26 (5)°. In the crystal, mol-ecules are linked via C-H⋯O hydrogen bonds into chains propagating along the b axis. A short O⋯C contact of 2.9972 (13) Šis observed.

Ethyl 2-[(2,4-difluoro-phen-yl)hydrazinyl-idene]-3-oxobutano-ate.

The asymmetric unit of the title compound, C(12)H(12)F(2)N(2)O(3), contains two mol-ecules, both of which exist in an E conformation with respect to their C=N bonds [1.321 (6) and 1.310 (6) Å]. The mol-ecular conformations are supported by intra-molecular N-H⋯O hydrogen bonds, which generate S(6) rings. In the crystal, mol-ecules are linked by C-H⋯O and C-H⋯F hydrogen bonds into layers lying parallel to (001). The crystal studied was an inversion twin with a 0.58 (1):0.42 (1) domain ratio.

Ethyl 2-[2-(2-meth-oxy-phen-yl)hydrazinyl-idene]-3-oxobutano-ate.

In the title compound, C(13)H(16)N(2)O(4), an intra-molecular N-H⋯O hydrogen bond generates an S(6) ring. The mol-ecule adopts an E configuration with respect to the central C=N double bond. In the crystal, symmetry-related mol-ecules are connected into chains along [010] via weak C-H⋯N hydrogen bonds. The crystal structure is further stabilized by weak C-H⋯π inter-actions.

4-[2-(4-Chloro-phen-yl)hydrazinyl-idene]-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-1-carbothio-amide.

In the title mol-ecule, C(11)H(10)ClN(5)OS, an intra-molecular N-H⋯O hydrogen forms an S(6) ring motif. The dihedral angle between the pyrazole ring and the benzene ring is 3.77 (8)°. In the crystal, mol-ecules are linked by N-H⋯S and N-H⋯O hydrogen bonds into layers parallel to the bc plane.

3-Methyl-5-phen-oxy-1-phenyl-1H-pyrazole-4-carbaldehyde.

In the title compound, C(17)H(14)N(2)O(2), the pyrazole ring makes dihedral angles of 73.67 (4) and 45.99 (4)°, respectively, with the adjacent phenyl and phen-oxy rings. In the crystal, there are no classical hydrogen bonds, but a weak C-H⋯π inter-action is observed.

4-[2-(4-Bromo-phen-yl)hydrazinyl-idene]-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-1-carbothio-amide.

In the title compound, C(11)H(10)BrN(5)OS, the approximately planar pyrazole ring [maximum deviation = 0.014 (2) Å] forms a dihedral angle of 5.49 (13)° with the benzene ring. An intra-molecular N-H⋯O hydrogen bond generates an S(6) ring motif. In the crystal, mol-ecules are linked through inter-molecular N-H⋯S and N-H⋯O hydrogen bonds, forming a two-dimensional network parallel to (100). A short Br⋯Br contact of 3.5114 (6) Šis also observed.

4-[2-(2-Meth-oxy-phen-yl)hydrazinyl-idene]-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-1-carbothio-amide.

In the title mol-ecule, C(12)H(13)N(5)O(2)S, a bifurcated intra-molecular N-H⋯O(O) hydrogen bond forms two S(6) ring motifs. The benzene ring forms a dihedral angle of 14.36 (11)° with the pyrazole ring. In the crystal, pairs of N-H⋯S hydrogen bonds form centrosymmetric dimers, generating R(2) (2)(8) ring motifs, which stack along the b axis.

Ethyl 2-[2-(3-meth-oxy-phen-yl)hydrazinyl-idene]-3-oxobutano-ate.

The title compound, C(13)H(16)N(2)O(4), is approximately planar (r.m.s. deviation = 0.065 Šfor the 19 non-H atoms). An intra-molecular N-H⋯O hydrogen bond generates an S(6) ring motif and the mol-ecule adopts an E conformation with respect to the central C=N double bond. In the crystal, pairs of inter-molecular C-H⋯O hydrogen bonds link adjacent mol-ecules into inversion dimers. The crystal structure also features weak C-H⋯π inter-actions.

3-Methyl-5-oxo-4-(2-phenyl-hydrazinyl-idene)-4,5-dihydro-1H-pyrazole-1-carbothio-amide.

In the title compound, C(11)H(11)N(5)OS, the pyrazole ring is approximately planar, with a maximum deviation of 0.010 (2) Å. The dihedral angles between the benzene ring and the pyrazole and carbothio-amide groups are 5.42 (9) and 10.61 (18)°, respectively. An intra-molecular N-H⋯O hydrogen bond generates an S(6) ring motif. In the crystal, mol-ecules are connected by inter-molecular N-H⋯O and C-H⋯S hydrogen bonds, forming R(2) (2)(12) ring motifs. In addition, there is a π-π stacking inter-action [centroid-centroid distance = 3.5188 (11) Å] between the pyrazole and benzene rings. These inter-actions link the mol-ecules into infinite chains along [001].

4-[(2,4-Difluoro-phen-yl)hydrazinyl-idene]-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-1-carbothio-amide.

In the title compound, C(11)H(9)F(2)N(5)OS, the pyrazole ring forms a dihedral angle of 16.42 (6)° with the benzene ring. Intra-molecular N-H⋯O hydrogen bonds generate two S(6) ring motifs. In the crystal, an R(2) (2)(8) ring motif is formed by a pair of inter-molecular N-H⋯S hydrogen bonds. Inter-molecular C-H⋯F hydrogen bonds further link the mol-ecules into a three-dimensional network.

2,3-Dibromo-3-(5-nitro-2-fur-yl)-1-(4-nitro-phen-yl)propan-1-one.

In the title compound, C(13)H(8)Br(2)N(2)O(6), the 2-furyl ring is essentially planar, with a maximum deviation of 0.002 (2) Å. It is inclined at an angle of 33.94 (9)° to the benzene ring. Both nitro groups are slightly twisted away from their attached rings; the dihedral angles are 4.6 (2)° between the nitro group and the 2-furyl ring, and 13.72 (19)° between the nitro group and the benzene ring. In the crystal, mol-ecules are linked into chains along [110] and [10] via two pairs of inter-molecular C-H⋯O hydrogen bonds, displaying R(2) (2)(10) ring motifs.

2,3-Dibromo-1,3-bis-(4-chloro-phen-yl)propan-1-one.

In the title compound, C(15)H(10)Br(2)Cl(2)O, the terminal benzene rings make a dihedral angle of 31.1 (2)° with each other. In the crystal, mol-ecules are stacked along the a axis and consolidated by C-H⋯π inter-actions. Short Cl⋯Cl [3.1140 (17) Å] and Br⋯Cl [3.4565 (13) Å] contacts are observed.