lantadene-b and rehmannic-acid

The new series of pentacyclic triterpenoids reduced lantadene A (3), B (4), and 22β-hydroxy-3-oxo-olean-12-en-28-oic acid (5) analogs were synthesized and tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead analog (11) showed sub-micromolar activity against TNF-α induced activation of NF-κB and exhibited inhibition of IKKβ in a single-digit micromolar dose. At the same time, 11 showed promising cytotoxicity against A549 lung cancer cells with IC50 of 0.98 μM. The Western blot analysis further showed that the suppression of NF-κB activity by the lead analog 11 was due to the inhibition of IκBα degradation, a natural inhibitor of NF-κB. The physicochemical evaluation demonstrated that the lead analog 11 was stable in the simulated gastric fluid of pH 2, while hydrolyzed at a relatively higher rate in the human blood plasma to release the active parent moieties. Molecular docking analysis showed that 11 was hydrogen bonded with the Arg-31 and Gln-110 residues of the IKKβ.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Molecular Docking Simulation; Molecular Structure; NF-kappa B; Oleanolic Acid; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

The antitumor pentacyclic triterpenoids, Lantadene A (1) and B (2) were isolated from the leaves of weed Lantana camara L. (Verbenaceae) and were structurally transformed to bioactive intermediates 3-6. The Claisen-Schmidt reaction of 22β-hydroxy-3-oxoolean-12-en-28-oic acid (5) with requisite aldehydes afforded 2-arylidene-22β-hydroxy-3-oxoolean-12-en-28-oic acids (7-16). The compounds were evaluated for their in-vitro anticancer activity by National Cancer Institute (NCI), USA and some of these compounds showed marked cytotoxicity in micromolar range. The mean graph midpoint (MG_MID) value of compound 3 (MG_MID -5.69) was higher than standard drug cisplatin (MG_MID -5.66) while comparable in case of compound 12 (MG_MID -5.52). The NCI's COMPARE molecular mechanistic analysis showed that these compounds were in significant correlations with activity patterns of mechanistic set of compounds (PCC ≥ 0.60).

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Oleanolic Acid; Structure-Activity Relationship

The ring A and D substituted analogs of pentacyclic triterpenoid Lantadene A (1) and B (2) were synthesized and evaluated for in vitro anticancer activity against four human cancer cell lines (HL-60, MCF-7, A549 and HCT-116). Analogs 3, 4, 7 and 8 showed enhanced inhibitory activity as compared with 1 and 2. These analogs were found more active than standard drug cisplatin with selective toxicity towards cancer cells and were inactive against normal cells (VERO). Furthermore, the mechanistic studies to investigate the effects of the new compounds on Akt protein in lung cancer cell line A549 and the NF-κB signalling pathway suggested that the compounds may exert their inhibitory activity on cancer cells through inhibition of both Akt and NF-κB activation. The docking studies of most potent analog (7) with 3D crystal structure of the nuclear factor kappa-B (NF-κB) P50 homodimer (PDB ID: 1NFK) revealed that carbonyl group of ester side chain and C-28 carboxylic acid groups were mainly involved in hydrogen bonding interaction. The oleanane frameworks was involved in strong hydrophobic interaction with amino acid phenylalanine and structure of lead compound have the potential to be developed as potent NF-κB inhibitor and anticancer agent.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chlorocebus aethiops; Humans; Molecular Docking Simulation; Neoplasms; NF-kappa B; Oleanolic Acid; Proto-Oncogene Proteins c-akt; Signal Transduction; Vero Cells

In this study, crude lantadene was extracted from Lantana canmara leaves, and its antifeeding effects on Plutella xylostella and Spodoptera litura larvae were tested. In no-choice test, crude lantadene at 1.6 mg x ml(-1) concentration had antifeeding effects on the 2nd instar P. xylostella larvae and 1st instar S. litura larvae, with the antifeeding rate being 62.4% and 33.1%, respectively within 48 h. In choice test, even a low concentration (0.4 mg x ml(-1)) crude lantadene still had anti-feeding effects on the 2nd instar P. xylostella larvae, and the antifeeding rate at 0.4, 0.8 and 1.6 mg x ml(-1) concentration was 52.7%, 55.5% and 78.9%, respectively. Crude lantadene only at 1.6 mg x ml(-1) concentration had anti-feeding effects on the 1st instar S. litura larvae, and the antifeeding rate was 33.0%. For the 2nd instar S. litura larvae, crude lantadene had no antifeeding effects both in no-choice and in choice test.

Topics: Animals; Feeding Behavior; Lantana; Larva; Moths; Oleanolic Acid; Pest Control, Biological; Plant Leaves; Spodoptera

Oral administration of lantana (Lantana camara var. aculeata) leaf powder to guinea pigs at a dose of 6 g/ kg body weight elicited cholestasis. The animals were euthanized 48 h after dosing. Liver homogenates, bile, gall bladder, blood, urine, contents of gastrointestinal tract (GIT) and faeces were analysed for the principal hepatotoxin in lantana leaves viz. lantadene A (LA), its congeners and biotransformation products, using high performance liquid chromatographic technique. Lantadenes could not be detected in liver, bile, gall bladder, blood and urine samples. LA and lantadene B (LB), their derivatives reduced lantadene A (RLA), reduced lantadene B (RLB) and two unidentified metabolites could be detected in the contents of lower GIT and faeces. In vitro incubation of lantana leaf powder with guinea pig caecal contents under anaerobic conditions elicited biotransformation of LA and LB to RLA and RLB, respectively. On the other hand, incubation of lantana leaf powder with cattle rumen liquor under anaerobic conditions did not elicit biotransformation of lantadenes.

Topics: Anaerobiosis; Animals; Bilirubin; Biotransformation; Cecum; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Guinea Pigs; Oleanolic Acid; Plant Leaves; Plants, Toxic

A toxin fraction was obtained from Lantana camara L (red variety) leaves by batch extraction and column chromatography on silica gel (60-120 mesh). The main constituents of the toxin preparation were lantadene A and lantadene B and it was devoid of reduced lantadene A. Oral administration (125 mg/kg bwt) of the toxin to male and female guinea pigs caused icterus and photosensitization within 48 hr. All the affected animals had hepatomegaly and significant increases in conjugated and unconjugated bilirubin in blood plasma. The intoxicated animals of either sex had marked increases in acid phosphatase activity which was inhibited 45.77% and 49.35% by 1 mM tartrate in male and female animals respectively. The corresponding inhibition of acid phosphatase activity in control male and female guinea pigs was 15.91% and 20.33% respectively.

Topics: Acid Phosphatase; Animals; Behavior, Animal; Bilirubin; Female; Guinea Pigs; Liver; Male; Oleanolic Acid; Plant Extracts; Sapogenins; Toxins, Biological

Topics: Humans; Lantana; Oleanolic Acid; Oxygen