angucyclinone and Neoplasms

Covering: 1997 to 2010. The angucycline group is the largest group of type II PKS-engineered natural products, rich in biological activities and chemical scaffolds. This stimulated synthetic creativity and biosynthetic inquisitiveness. The synthetic studies used five different strategies, involving Diels-Alder reactions, nucleophilic additions, electrophilic additions, transition-metal mediated cross-couplings and intramolecular cyclizations to generate the angucycline frames. Biosynthetic studies were particularly intriguing when unusual framework rearrangements by post-PKS tailoring oxidoreductases occurred, or when unusual glycosylation reactions were involved in decorating the benz[a]anthracene-derived cores. This review follows our previous reviews, which were published in 1992 and 1997, and covers new angucycline group antibiotics published between 1997 and 2010. However, in contrast to the previous reviews, the main focus of this article is on new synthetic approaches and biosynthetic investigations, most of which were published between 1997 and 2010, but go beyond, e.g. for some biosyntheses all the way back to the 1980s, to provide the necessary context of information.

Topics: Aminoglycosides; Anthraquinones; Anti-Bacterial Agents; Biological Products; Biosynthetic Pathways; Carbohydrate Sequence; Cell Line, Tumor; Coumarins; Glycosides; Glycosylation; Humans; Isoquinolines; Molecular Structure; Naphthoquinones; Neoplasms; Polyketides; Quinones; Streptomyces; Structure-Activity Relationship

Cancer is the second cause of death in the world after cardiovascular diseases. Cancer cells acquire capacities not present in normal cells, such as self-sufficiency, resistance to antiproliferative stimuli, evasion of apoptosis, unlimited replication, invasiveness and metastasis. Consequently, it is of major interest to explore and develop molecules with anticancer activity directed to specific targets. In this study, we aimed to evaluate two series of polycyclic quinones: aza-angucyclinone and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones, in their capacity to inhibit human topoisomerase I (TOP1) and to trigger apoptosis through activation of caspase-3. We evaluated the capacity of the two series of polycyclic quinones to inhibit TOP1, using a DNA supercoiled relaxation assay and their capacity to induce apoptosis through the activation of caspase-3 in HL60 cells. Both series of quinones inhibited TOP1 activity over 50%. When we evaluated the pro-apoptotic capacity of both series of quinones, at therapeutically relevant concentrations, the arylaminoquinones ADPA-1CC (methyl 7-(4-methoxyphenyl)amino-1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylate), P4 (9-phenylamino-3,4-dihydrophenanthridine-1,7,10(2H)-trione) and the aza-angucyclinone OH-6H (8-hydroxy-2,4-dimethyl-2H,4H-benzo[g]pyrimido[4,5-c]isoquinoline-1,3,7,12-tetraone) increased the caspase-3 activity by approximately 2-fold over the control. The series of the arylaminoquinones and aza-angucyclinones showed differential antiproliferative capacity. We further identified a group of them that showed antiproliferative capacity possibly through inhibition of TOP1 and by activation of caspase-3. This group of molecules may represent a potential pharmacological tool in the treatment against cancer.

Topics: Anthraquinones; Apoptosis; Aza Compounds; Caspase 3; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type I; Enzyme Activation; HL-60 Cells; Humans; Neoplasms; Quinones; Topoisomerase I Inhibitors

Chemomicin (CHM), an angucyclinone antibiotic extracted from the fermentation broth of Nocardia Mediterranei subsp. Kanglensis 1747-64, shows immunosuppressive activity. However, whether it can inhibit growth of tumor cells remains elusive. In the present study, we show that CHM potently inhibited the proliferations of eight various types of human tumor cell lines and non-cross resistant to multidrug-resistant cells. In contrast to action of doxorubicin, the generation of reactive oxygen species was observed as early as 30 min after addition of CHM and its process did not involve iron. The apoptotic cells with chromatin condensation and Annexin V staining markedly increased after the human hepatoma HepG2 was exposed to 1, or 2 microg/ml CHM for 24 h. In the CHM-induced apoptosis, robust increment of p53 expression, activation of caspase-3, -7, -8, -9, cleavage of PARP and the phosphorylation of p38 and JNK, were detected by Western blot analysis. Further investigation revealed the disruption of mitochondrial membrane potential in the cells with CHM incubation for 4 h. Taken together, the results demonstrated that potent proliferation inhibitory effect of CHM on tumor cells is due to activation of the apoptotic pathway.

Topics: Anthraquinones; Anti-Bacterial Agents; Antineoplastic Agents; Apoptosis; Cell Division; Cell Proliferation; Drug Evaluation, Preclinical; G2 Phase; HCT116 Cells; Humans; Membrane Potential, Mitochondrial; Models, Biological; Neoplasms; Reactive Oxygen Species; Signal Transduction; Tumor Cells, Cultured