The present study highlights the biological effects of chromomycin A2 toward metastatic melanoma cells in culture. Besides chromomycin A2, chromomycin A3 and demethylchromomycin A2 were also identified from the extract derived from Streptomyces sp., recovered from Paracuru Beach, located in the northeast region of Brazil. The cytotoxic activity of chromomycin A2 was evaluated across a panel of human tumor cell lines, which found IC50 values in the nM-range for exposures of 48 and 72 h. MALME-3M, a metastatic melanoma cell line, showed the highest sensitivity to chromomycin A2 after 48h incubation, and was chosen as a model to investigate this potent cytotoxic effect. Treatment with chromomycin A2 at 30 nM reduced cell proliferation, but had no significant effect upon cell viability. Additionally, chromomycin A2 induced accumulation of cells in G0/G1 phase of the cell cycle, with consequent reduction of S and G2/M and unbalanced expression of cyclins. Chromomycin A2 treated cells depicted several cellular fragments resembling autophagosomes and increased expression of proteins LC3-A and LC3-B. Moreover, exposure to chromomycin A2 also induced the appearance of acidic vacuolar organelles in treated cells. These features combined are suggestive of the induction of autophagy promoted by chromomycin A2, a feature not previously described for chromomycins.

A investigação química das raízes de Cordia polycephala resultou no isolamento de duas novas naftoquinonas terpenoídicas, 6-[10-(12,12-dimetil-13α-(22-metil-21-butenoilóxi -[10-(12,12-dimetil-13α-(tigloilóxi)-16-metenilciclohexil)etil]-naftaleno-1,4-diona, designadas de cordiaquinonas N (1) e O (2), respectivamente. As cordiaquinonas já conhecidas, B (3), L (4) e E (5), foram também isoladas. Suas estruturas foram elucidadas após detalhada análise dos dados de RMN 1 H e 13 C (1D e 2D) e EMAR (espectrometria de massas de alta resolução). Todas as cordiaquinonas (1-5) foram avaliadas contra quatro linhagens de células cancerígenas: HCT-8 (colo), HL-60 (leucemia), MDA-MB-435 (melanoma) e SF295 (glioblastoma), mostrando IC 50 na faixa de 1,2 a 11,1 mmol L -1 . As novas cordiaquinonas 1 e 2 foram as mais ativas contra todas as linhagens de câncer, enquanto 3 foi mais seletiva para células leucêmicas (IC 50 2,2 μmol L -1 ).The chemical investigation of roots of Cordia polycephala resulted in the isolation of two new terpenoid naphtoquinones, 6-[10-(12,12-dimethyl-13α-(22-methyl-21-butenoyloxy)-16-methenylcyclohexyl)ethyl]-naphtalene-1,4-dione and (6-[10-(12,12-dimethyl-13α-(tigloyloxy)-16-methenylcyclohexyl)ethyl]-naphtalene-1,4-dione, named as cordiaquinone N (1) and O (2), respectively. The known cordiaquinones B (3), L (4) and E (5) were also isolated. Their structures were elucidated after detailed 1D and 2D NMR and high resolution electrospray ionization mass spectrometry (HRESIMS) data analysis. All cordiaquinones (1-5) were evaluated against four human cancer cell lines: HCT-8 (colon), HL-60 (leukemia), MDA-MB-435 (melanoma) and SF295 (glioblastoma), showing IC 50 values in the range of 1.2 to 11.1 mmol L -1 . The new cordiaquinones 1 and 2 were the most active against all cancer cell lines, while compound 3 was selective to leukemia HL-60 cells (IC 50 2.2 mmol L -1 ).

Discovered in the late 1940s, the pyrrolinonodithioles represent a family of potent disulfide-containing natural products. Although they are understood in a synthetic and biosynthetic context, the biological role of these materials remains unresolved. To date, their activity has been suggested to arise through regulating RNA metabolism, and more recently they have been suggested to function as backup thiols for detoxification. Using materials identified through a natural products program, we now identify the biological function of one member of this family, pyrroloformamide, as an antimitotic agent acting, in part, by disrupting cytokinesis.

Continuing search for anticancer compounds from the marine environment, we have studied microorganisms that inhabit intertidal sediments of the northeastern Brazilian coast. Of the 32 strains isolated, 13 were selected for biological evaluation of their crude extracts. The acetate extract obtained from a Gram-negative bacterium was strongly active against cancer cell lines with IC(50) values that ranged from 0.04 (HL60 leukemia cells) to 0.26 μg/ml (MDA MB-435 melanoma cells). The bacterium was identified as a Pseudoalteromonas sp. based on 16S rRNA gene sequencing. A bioassay-guided fractionation of the active extract led to the isolation of prodigiosin, a well-known tripyrrole red pigment with immunosuppressive and anticancer activities. Further experiments with ErbB-2 overexpressing cell lines, including HB4a-C3.6 (moderate overexpression), HB4a-C5.2 (high overexpression), and the parental HB4a cell line, were performed. Prodigiosin was moderately active toward HB4a cells with an IC(50) of 4.6 μg/ml, while it was 115 and 18 times more active toward HB4a-C3.6 cells (IC(50) of 0.04 μg/ml) and HB4a-C5.2 (IC(50) of 0.26 μg/ml) cells, respectively. These data suggest that, in spite of its previously described apoptosis-inducing properties, prodigiosin can selectively recognize cells overexpressing ErbB-2, which could be highly appealing in human breast cancer therapy.

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