Evelyne Alves Santos

Amphidinolides are cytotoxic macrolides produced by symbiotic unicellular microalgae of the genus Amphidinium. Here we describe the identification of four related molecules belonging to this macrolide family isolated from the invertebrate Stragulum bicolor. The new molecules, named amphidinolide PX1-PX3 and stragulin A (1–4), show an unprecedented carbon skeleton whose complete stereochemistry has been determined by spectroscopic and computational methods. Differences in the structures of these molecules modulate their biological activity in a panel of tumor cell lines, but the opened derivative stragulin (4) shows a very potent and specific cytotoxic activity (IC₅₀ 0.18 µM) against the aggressive human melanoma cell A2058.

Natural products discovered by using agnostic approaches, unlike rationally designed leads or those obtained through high‐throughput screening, offer the ability to reveal new biological pathways and, hence, serve as an important vehicle to unveil new avenues in drug discovery. The ritterazine–cephalostatin family of natural products displays robust and potent antitumor activities, with sub‐nanomolar growth inhibition against multiple cell lines and potent activity in xenograft models. Herein, we used comparative cellular and molecular biological methods to uncover the ritterazine–cephalostatin cytotoxic mode of action (MOA) in human tumor cells. Our findings indicated that, whereas ritterostatin G_N1_N, a cephalostatin–ritterazine hybrid, binds to multiple HSP70s, its cellular trafficking confines activity to the endoplasmic reticulum (ER)‐based HSP70 isoform, GRP78. This targeting results in activation of the unfolding protein response (UPR) and subsequent apoptotic cell death.

Benthic cnidarians are colonial marine animals that host a rich population of associated and symbiotic microorganisms. In a recent paper we described for the first time the isolation of amphidinolide P (1) from the Brazilian octocoral Stragulum bicolor. Amphidinolides and similar compounds had been previously reported only from dinoflagellates of the genus Amphidinium; thus the presence of 1 in the invertebrate opens intriguing questions on the role and occurrence of these molecules in marine ecosystems. Here we report the identification of four further amphidinolides from the same soft coral, including the known amphidinolide T1 (2) and the new analogues here named amphidinolides C4 (3), B8 (4), and B9 (5). The chemical structures have been elucidated mainly by extensive study of spectroscopic data. Cytotoxic activities of 3 and 4 were evaluated against the colon adenocarcinoma cell line HCT-116.

Three new plakortides, 7,8-dihydroplakortide E (1), 2, and 10, along with known natural products 3, 4, spongosoritin A (5), 6–8, and plakortide P (9), were isolated from Brazilian specimens of Plakortis angulospiculatus. Compounds 2, 3, 5, and 7–9 displayed cytotoxic activities with IC₅₀ values ranging from 0.2 to 10 μM. Compounds that contained a dihydrofuran ring were generally less active and displayed time dependence in their activity. The activities of compounds 2 and 7–9, carboxylic acids bearing a common six-membered endoperoxide, were higher overall than for compounds 3 and 5. The modes underlying the cytotoxic actions of plakortides 2, 3, 5, 7, and 9 were further investigated using HCT-116 cells. While dihydrofurans 3 and 5 induce a G₀/G₁ arrest, six-membered peroxides 2, 7, and 9 delivered a G₂/M arrest and an accumulation of mitotic figures, indicating a distinctly different antimitotic response. Confocal analysis indicated that microtubules were not altered after treatment with 2, 7, or 9, therein suggesting that the mitotic arrest may be unrelated to cytoskeletal targets. Overall, we find that two related classes of natural products obtained from the same extract offer cytostatic activity, yet they do so through discrete pathways.

Lippia microphylla Cham. (Verbenaceae) is an endemic underexploited Brazilian vegetal. This work reviewed the biological potentialities of Lippia microphylla, emphasizing the properties of essential oils (EOs) and analyzed scientific indicators about genus Lippia and L. microphylla. Databases from 1948 to the present were searched and a software (vantage point 7.1) associated with Derwent Innovation Index was used to identify the indicators of the genus Lippia, and biological activities and compounds in the L. macrophylla species. Ethnopharmacological records report use of L. microphylla leaves to treat gastrointestinal disorders, influenza, bronchitis, cough, nasal congestion, and sinusitis during vaporization, whose aromatic volatile oils are rich in monoterpenes, especially cineole, terpineol, and thymol. Other EOs have larvicidal activity on Aedes aegypti larvae, and antifungal, antibacterial and cytotoxic and antitumor action on human and murine cancer cells. Brazil is the country with more articles about Lippia species, but it deposited only 9 patents since 1993. Most of the publications about L. microphylla are concentrated in food and chemical sciences. This bioprospection helps to choice areas of interest for capital investment and to give support for Brazilian Institutions to establish cooperation and improve technological impact at the point of view of creation and innovation.

A novel series of carbohydrate-based 1,2-naphthoquinones 13a–c and their substituted phenylhydrazono derivatives 14a–l were synthesized and evaluated for cytotoxicity against HL-60, MDA-MB435, HCT-116 and SF-295 cancer cell lines. The compounds 9a–c showed the best cytotoxicity profile (IC₅₀ below 2 μM) against HL-60 and MDA-MB 435 human cells, while the hydrazone derivative 14i (IC₅₀ HL-60 1.65 μM) was selective for leukemia when compared to the reference drug doxorubicin. None of the compounds exhibited lytic effects against mouse erythrocytes. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques (¹H, ¹³C-APT, COSY-¹H × ¹H and HETCOR ¹J_CH) and by elemental analysis.

A synthetic method to obtain α- and β-pyran naphthoquinones 10 and 11 with a hydroxyl substituent on the aromatic ring was developed. Two series of α- and β-pyran naphthoquinones were obtained from the 8-hydroxy-lawsone, and their anticancer properties were evaluated against four tumor cell lines. In general, the new compounds displayed good activity, possibly indicating that these compounds have increased pro-oxidant capacity. The 9-hydroxy-α-lapachone and 7-hydroxy-β-lapachone analogues of the natural products α-lapachone and β-lapachone were successfully produced by this methodology.

A series of eleven (E)-2-benzothiazole hydrazones were synthesized and evaluated for their in vitro anticancer activities against three neoplastic cancer cells: HL-60 (leukemia), MDAMB-435 (breast) and HCT-8 (colon). Two of them, 3e and 3f, showed good cytotoxicity activity for HL-60. The results also demonstrated that compound 3f seems to be selective to HL-60 cell line, appearing as a good prototype for an antileukemia lead molecule.