Semisynthetic and SAR Studies of Amide Derivatives of Neocrotocembraneic Acid as Potential Antitumor Agents.

A series of novel amide derivatives of cembranoid neocrotocembraneic acid were designed and synthesized. The antiproliferative activities of these derivatives were evaluated against three human tumor cell lines (the human cervical cancer cell line HeLa, chronic myeloid leukemia cell line K562 and leukemia multidrug-resistant cell line K562/A02). Some of the synthesized compounds exhibited moderate to good activity against all three cancer cell lines. Particularly, compound 8a exhibited more potent antiproliferative activity than the reference drug etoposide against drug-resistant cell line K562/A02, indicating that it possessed a great potential for further development as a multidrug resistance modulator by structural modification.

Synthesis and Evaluation of New Podophyllotoxin Derivatives with in Vitro Anticancer Activity.

A series of novel podophyllotoxin derivatives were designed and synthesized. The cytotoxic activities of these compounds were tested against three tumor cell lines (HeLa, K562, and K562/A02). Most of the derivatives (IC50 = 1-20 µM) were found to have stronger cell growth inhibitory activity than positive control etoposide. Among them, 4ß-N-[(E)-(5-((4-(4-nitrophenyl)-piperazin-1-yl)methyl)furan-2-yl)prop-2-en-1-amine]-4-desoxy-podophyllotoxin (9l) demonstrated significant inhibitory activity against HeLa, K562, and K562/A02 cell lines with IC50 values of 7.93, 6.42, 6.89 µM, respectively.

Synthesis and evaluation of novel podophyllotoxin derivatives as potential antitumor agents.

Cancer multidrug resistance (MDR) is a common cause of treatment failure in cancer patients. Increased expression of permeability glycoprotein (P-gp), which is also known as MDR-1, is the main cause of multidrug resistance. Podophyllotoxin derivatives hold great promise in the battle to overcome multidrug resistance, as they can induce cytotoxicity through multiple mechanisms. Here, we synthesized sixteen novel podophyllotoxin derivatives and evaluated their cytotoxicities in human cancer cell lines, HeLa, K562 and K562/A02. Some of these compounds were more potent than etoposide, a clinically relevant inhibitor of DNA repair enzymes. In particular, compound 5p exhibited the most potent activity toward drug-resistant K562/A02 cells, as it robustly inhibited tumor cell proliferation and induced apoptosis. Furthermore, preliminary investigation suggested that 5p inhibited the expression of MDR-1 in K562/A02 cells more effectively than etoposide.

Metabolic pathways involved in Xin-Ke-Shu protecting against myocardial infarction in rats using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

Xin-Ke-Shu (XKS) is a patent drug used for coronary heart diseases in China. This study evaluated the protective effect of XKS against isoproterenol (ISO)-induced myocardial infarction (MI). For its underlying mechanism in rats with MI, a metabonomic approach was developed using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/QTOF-MS). Plasma metabolites were profiled in MI rats, pretreated orally with or without XKS. Two genres of metabolic biomarkers were used to elucidate the pharmacological action of XKS: pathological biomarkers and pharmaco biomarkers. Fifteen metabolites significantly varying between MI rats and normal rats were characterized as potential pathological biomarkers related to MI, including L-acetylcarnitine (1), L-isoleucyl-L-proline (2), tyramine (3), isobutyryl-L-carnitine (4), phytosphingosine (5), sphinganine (6), L-palmitoylcarnitine (7), lysoPC(18:0) (8), uric acid (9), L-tryptophan (10), lysoPC(18:2) (11), lysoPC(16:0) (12), docosahexaenoic acid (13), arachidonic acid (14) and linoleic acid (15). Among them, eight (1-6, 9 and 10) were first reported as pathological biomarkers related to ISO-induced MI, which mainly involved into fatty acid ß-oxidation pathway, sphingolipid metabolism, proteolysis, tryptophan metabolism and purine metabolism. The metabolites significantly varying between MI rats with and without XKS pretreatment were considered as pharmaco biomarkers. A total of 17 pharmaco biomarkers were recognized, including 15 pathological biomarkers (1-15), hexanoylcarnitine (16) and tetradecanoylcarnitine (17). The results suggested that pretreatment of XKS protected metabolic perturbations in rats with MI, major via lipid pathways, amino acid metabolism and purine metabolism, which also provided a promising approach for evaluating the pharmacodynamics and mechanism of traditional Chinese medicines (TCM) formulas.

2-Cyano-2-methyl-propanamide.

In the crystal structure of the title compound, C(5)H(8)N(2)O, mol-ecules are linked via pairs of N-H⋯O hydrogen bonds, forming inversion dimers. These dimers are linked via pairs of N-H⋯H hydrogen bonds into zigzag chains propagating along [101].

2-Chloro-5-chloro-meth-yl-1,3-thia-zole.

In the title compound, C(4)H(3)Cl(2)NS, the chloro-methyl C and 2-position Cl atoms lie close to the mean plane of the thia-zole ring [deviations = 0.0568 (2) and 0.0092 (1) Å, respectively]. No classical hydrogen bonds are found in the crystal structure.

N-Ethyl-3,5-dinitro-benzamide.

In the title mol-ecule, C(9)H(9)N(3)O(5), the dihedral angle between the mean planes of the amide group and the benzene ring is 31.24 (14)°. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules to form one-dimensional chains propagating in [100].

2-(o-Tol-yloxy)benzoic acid.

In the crystal structure of the title compound, C(14)H(12)O(3), mol-ecules are linked via inter-molecular O-H⋯O hydrogen bonds, resulting in dimer formation. The dihedral angle between the two phenyl rings is 76.2 (2)°.

N,4-Dimethyl-benzamide.

In the crystal of the title compound, C(9)H(11)NO, mol-ecules are connected via inter-molecular N-H⋯O hydrogen bonds, forming a one-dimensional network in the b-axis direction. The dihedral angle between the amide group and the benzyl ring is 13.8 (2)°.

2-Amino-4-(3-fluoro-phen-yl)-6-(naphthalen-1-yl)pyridine-3-carbonitrile.

There are two independent mol-ecules in the asymmetric unit of the title compound, C(22)H(14)FN(3), which differ slightly in the relative orientations of the naphthyl and phenyl groups with respect to the pyridyl ring framework. In one mol-ecule, the naphthyl ring system and the phenyl ring form dihedral of angles 56.50 (2) and 48.23 (3)°, respectively, with the pyridyl ring plane. In the other mol-ecule, the corresponding dihedral angles are 50.01 (2) and 51.1 (3)°, respectively. In the crystal, inter-molecular N-H⋯N hydrogen bonds connect the independent mol-ecules into dimers.

1-Methyl-3-trifluoro-methyl-1H-pyrazol-5-ol.

In the title compound, C(5)H(5)F(3)N(2)O, the F atoms are disordered over two sets of sites in a 0.64 (3):0.36 (3) ratio. In the crystal structure, O-H⋯N hydrogen bonds link the mol-ecules into chains and a short C-H⋯F contact also occurs.

2-Methyl-4-trifluoro-meth-yl-1,3-thia-zole-5-carboxylic acid.

In crystal of the title compound, C(6)H(4)F(3)NO(2)S, mol-ecules are linked by O-H⋯N and C-H⋯O hydrogen bonds, forming chains.