Creosote bush lignans for human disease treatment and prevention: Perspectives on combination therapy.

The medicinal properties of the most successful plant in the deserts of the western hemisphere, the creosote bush (Larrea tridentata), are evidenced by the long traditional usage of the plants by the Native Americans Indian tribes in Southwestern North America and the Amerindians from South America. The plant is rich in simple bisphenyl lignans and tricyclic lignans known as cyclolignans. These compounds are responsible for many of the pharmacological activities of extracts of the plants. Some of these activities, namely antiherpes, antioxidant, antifungal, and anti-inflammatory, were known a century ago. Only recently have further studies revealed other crucial activities of the same plant molecules as powerful agents against human immunodeficiency virus, human papillomavirus, cancer, neurodegenerative diseases, and symptoms of aging. Molecular mechanisms underlying the antiviral and anticancer activities have been elucidated and involve the inhibition of SP1 dependent gene transcription. This review summarizes the recent findings on creosote bush lignans. We introduce the concept of a cocktail of safe well-characterized natural products from the creosote bush that would represent a bridge between oriental herbal medicines and Western drug-based therapies.

Hepatocellular carcinoma targeting agents: conjugates of nitroimidazoles with trimethyl nordihydroguaiaretic acid.

Cancer has been a primary global health issue for decades, with hepatocellular carcinoma (HCC) resulting in more than half a million new cases annually. With survival rates as low as <5% after five years, it remains a poorly treated cancer. Nordihydroguaiaretic acid (NDGA), an antioxidant, was previously proven effective against cancer cells. Nitroimidazole derivatives convert into reactive compounds under hypoxic conditions. In this study, eight methylated NDGAs containing a 2- or 4-nitroimidazole moiety were synthesized as leads against HCC. Four of these conjugates, possessing a poly(ethylene glycol) tether, had superior aqueous solubility. These four NDGA-nitroimidazole conjugates were found to inhibit the proliferation HCC Hep3B cells with IC50 values between 10 and 15 µM. Furthermore, nitroimidazole-conjugated NDGA derivatives exhibit better antiproliferative activity under hypoxic conditions.

Isolation of lignans from Schisandra chinensis with anti-proliferative activity in human colorectal carcinoma: Structure-activity relationships.

Separate benzocyclooctadiene lignans were isolated from the berries of Schisandra chinensis in milligram quantities on analytical reverse phase (RP) HPLC by an automated repeat-injection method and shown to have anti-proliferative activity against human colorectal cancer cells. Structures of the compounds were determined by a combination of NMR and mass spectrometry. Stereospecific NMR assignments for gomisin-N and deoxyschisandrin, gave more complete and accurate data than previously reported, based on 600MHz 2D HSQC, DQF-COSY and HMBC data. Comparison of coupling constants and HMBC crosspeak intensities with calculated and X-ray crystal structures confirmed their stereochemistry and conformation. Analysis of structure-activity relationships revealed the importance of key structural determinants. The S-biphenyl configuration of gomisin N, the most active lignan, correlated with increased anti-proliferative activity, while the presence of a hydroxyl group at the C7 position reduced or abolished this activity. Increased activity was also observed when a methylenedioxy group was present between C12 and C13. The percent yield of the most active compounds relative to the starting plant materials was 0.0156% for deoxyschisandrin and 0.0173% for gomisin N. The results of these studies indicate that automated repeat-injection method of analytical HPLC may provide a superior alternative to the standard semi-preparative HPLC techniques for separation of complex mixtures.

Novel antiviral agent tetraglycylated nordihydroguaiaretic acid hydrochloride as a host-dependent viral inhibitor.

A water soluble derivative of nordihydroguaiaretic acid (NDGA), G(4)N (2), synthesized by reaction of NDGA (1) with N,N-dimethylglycine in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine and then with HCl(g) (Scheme 1), competes effectively with the DNA binding domain of recombinant Sp1 protein for binding to the human immunodeficiency virus (HIV) LTR as demonstrated by an electrophoretic mobility-shift assay (EMSA). By blocking Sp1 binding to the HIV LTR, G(4)N suppresses Sp1-regulated HIV Tat transactivation and replication in cultured cells with an IC(50) of 12 microM similar to that of 3'-O-methyl-NDGA as we have previously reported. In addition simian immunodeficiency virus (SIV) replication was completely inhibited by G(4)N at 5.0 microM. G(4)N showed no toxic effect to 174 x CEM cells and H9 cells at 100 microM.

Antiviral saponins from Tieghemella heckelii.

Arganine C (1) and a new saponin, tieghemelin (2), were isolated from Tieghemella heckelii fruits. Arganine C (1) strongly inhibited HIV entry into cells in a cell fusion assay. The less potent tieghemelin (2) was converted into arganine C (1) by reduction of its ethyl ester with sodium borohydride. The removal of the four-sugar chains from arganine C (1) and tieghemelin (2) to give 16alpha-hydroxyprotobassic acid 3-O-beta-D-glucopyranoside (3) and 16alpha-hydroxyprotobassic acid 3-O-beta-D-glucuronopyranoside (4), respectively, caused total loss of activity in both cases. Arganine C (1) was not significantly cytotoxic to HeLa-CD4(+) cells at the level required to reduce the syncytium count to zero, suggesting it to be a promising candidate for further study as an antiviral drug.