Fatima Rivas

Antimalarial Evaluation of the Chemical Constituents of Hairy Root Culture of Bixa orellana L.

Over 216 million malaria cases are reported annually worldwide and about a third of these cases, primarily children under the age of five years old, will not survive the infection. Despite this significant world health impact, only a limited number of therapeutic agents are currently available. The lack of scaffold diversity poses a threat in the event that multi-drug–resistant strains emerge. Terrestrial natural products have provided a major source of chemical diversity for starting materials in many FDA approved drugs over the past century. Bixa orellana L. is a popular plant used in South America for the treatment of malaria. In search of new potential therapeutic agents, the chemical constituents of a selected hairy root culture line of Bixa orellana L. were characterized utilizing NMR and mass spectrometry methods, followed by its biological evaluation against malaria strains 3D7 and K1. The crude extract and its isolated compounds demonstrated EC50 values in the micromolar range. Herein, we report our findings on the chemical constituents of Bixa orellana L. from hairy roots responsible for the observed antimalarial activity.

Evaluation of Jatropha isabelli natural products and their synthetic analogs as potential antimalarial therapeutic agents.

Protozoal diseases such as malaria are a leading world health concern. We screened a library of fractionated natural products to identify new potential therapeutic leads and discovered that jatrophone (a product of Jatropha isabelli) exerts significant activity against Plasmodium falciparum strains 3D7 and K1. A focused jatrophone-scaffold library was synthesized to evaluate jatrophones mode of action and identify more selective analogs. Compounds 25 and 32 of this natural product-inspired compound library exhibited micromolar EC50 values against strains 3D7 and K1, thus providing a new antimalarial molecular scaffold. Our report describes an efficient derivatization approach used to evaluate the structure-activity relationship of jatrophone analogs in search of potential new antimalarial agents.

Antimalarial activity of abietane ferruginol analogues possessing a phthalimide group.

The abietane-type diterpenoid (+)-ferruginol, a bioactive compound isolated from New Zealands Miro tree (Podocarpus ferruginea), displays relevant pharmacological properties, including antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and anticancer. Herein, we demonstrate that ferruginol (1) and some phthalimide containing analogues 2-12 have potential antimalarial activity. The compounds were evaluated against malaria strains 3D7 and K1, and cytotoxicity was measured against a mammalian cell line panel. A promising lead, compound 3, showed potent activity with an EC50 = 86 nM (3D7 strain), 201 nM (K1 strain) and low cytotoxicity in mammalian cells (SI>290). Some structure-activity relationships have been identified for the antimalarial activity in these abietane analogues.

(+)-Dehydroabietylamine derivatives target triple-negative breast cancer.

Breast cancer remains the leading cause of cancer-related death among women. The invasive triple-negative subtype is unresponsive to estrogen therapy, and few effective treatments are available. In search of new chemical scaffolds to target this disease, we conducted a phenotypic screen against the human breast carcinoma cell lines MDA-MB-231, MA11, and MCF-7 using terrestrial natural products. Natural products that preferentially inhibited proliferation of triple-negative MDA-MB-231 cells over estrogen receptor-positive cells were further studied; herein we focused on the abietanes. The activity of the abietane carnosol prompted us to generate a focus library from the readily available (+)-dehydroabietylamine. The lead compound 61 displayed a promising EC50 of 9.0 μM against MDA-MB-231 and our mechanistic studies indicate it induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of PARP. Here we describe our current progress towards this promising therapeutic candidate.

Advances toward the Synthesis of Functionalized γ-Lactams

I. New Methodologies for the Synthesis of Functionalized g-Lactams..............257 1. Intramolecular Microwave-facilitated Cyclization Reaction ....................257 2. Zinc-promoted Aza-Barbier Reaction ...................................................257 3. Sugars as Chiral Pools for g-Lactams ..................................................258 4. Stereoselective Intramolecular Cyclization Reaction ..............................259 5. 1,3-Dipolar Cycloaddition Reaction ....................................................259 6. Intramolecular Azetidine Cascade Reaction ..........................................260 7. Michael Addition ..............................................................................260 8. Intramolecular Radical Cyclization .....................................................261 9. Oxidative Cyclization ........................................................................262 10. Intramolecular Radical Addition .........................................................263 11. Stereoselective Intramolecular Cyclization ...........................................263 12. Lewis Acid-mediated Reaction ............................................................264 13. Brønsted Acid mediated Reaction ........................................................265 14. Brønsted Acid Cooperative Catalysis ...................................................265 15. Gold-Cooperative Catalysis................................................................266 16. [3C2] Cyclization Reaction ................................................................266 17. Asymmetric g-Lactams from Sulfinylimino Esters ...................................267 18. Scandium-mediated Aldol-type Reaction...............................................268 19. Heteroatom Pauson-Khand Reaction ...................................................268 20. Rhodium C-H Insertion Reaction.........................................................269 21. Rhodium-mediated Intramolecular Reaction .........................................269 22. Rhodium-catalyzed Michael Additions .................................................270 23. Carbopalladation of Alkynamides........................................................271 24. Carbopalladation of Allenes ...............................................................271 25. Indium-mediated Conia-ene Reaction ..................................................272 26. Cyclization Reaction of Enals with N-Sulfonylimines ..............................273 27. Isocinchonidine-mediated Organocatalysis ...........................................273 28. Cascade Nucleophilic Cyclization Reaction ..........................................274 29. Brook Rearrangement and Cyclization Reaction ....................................276 30. Asymmetric Michael/Cyclization Cascade Reaction ...............................277 31. Asymmetric Mukaiyama Aldol Reaction................................................278

Anti-proliferative evaluation of monoterpene derivatives against leukemia

The cure rate of pediatric acute lymphoblastic leukemia (ALL) has significantly improved in the past thirty years, however not all patient cohorts respond well to current chemotherapy regimens. Among the high risk patient cohort is infants with MLL-rearranged (MLL-r) B-ALL, which remains dismal with an overall survival rate <35%. Our program is interested in identifying new molecular scaffolds to better understand the underlying mechanisms and ultimately provide new targeted treatments. Based on a phenotypic screen, phenolic natural products were identified as promising scaffolds for further chemical evaluation. Herein we disclose the effects of a potent anti-proliferative compound 31 against human ALL leukemia cellular models.

Synthesis and structure-activity relationship of disubstituted benzamides as a novel class of antimalarial agents.

Malaria is a devastating world health problem. Using a compound library screening approach, we identified a novel series of disubstituted benzamide compounds with significant activity against malaria strains 3D7 and K1. These compounds represent a new antimalarial molecular scaffold exemplified by compound 1, which demonstrated EC(50) values of 60 and 430 nM against strains 3D7 and K1, respectively. Herein we report our findings on the efficient synthesis, structure-activity relationships, and biological activity of this new class of antimalarial agents.

Synthesis and evaluation of colletoic acid core derivatives.

Cortisol homeostasis has been linked to the pathogenesis of metabolic syndrome (MetS), since it stimulates hepatic gluconeogenesis and adipogenesis. MetS is classified as a constellation of health conditions that increase the risk of type 2 diabetes and cardiovascular disease. Intracellular cortisol levels are regulated by 11β-hydroxysteroid dehydrogenase (type 1 and type 2) in a tissue dependent manner. The type 1 enzyme (11β-HSD1) is widely expressed in glucocorticoid targeted tissues and is responsible for the conversion of cortisone to the active cortisol. Local reduction of cortisol regeneration presents a potential strategy for MetS treatment. Recently we disclosed the total synthesis of (+)-colletoic acid as a potent 11β-HSD1 inhibitor. Herein, we describe our improved processing chemistry for the synthesis of the colletoic acid core to access a diverse number of derivatives for evaluation against 11β-HSD1. The Evans chiral auxiliary was utilized to construct the acyclic precursor 12 to afford the acorane core 9 using a modified Heck reaction in excellent chemical yields. The colletoic acid core derivatives showed modest activity against 11β-HSD1 and will serve for further biological evaluation.

Novel vitexin-inspired scaffold against leukemia

Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in children. Up to a quarter of ALL patients relapse and face poor prognosis. To identify new compound leads, we conducted a phenotypic screen using terrestrial natural product (NP) fractions against immortalized ALL cellular models. We identified vitexin, a flavonoid, as a promising hit with biological activity (EC50 = 30 μM) in pre-B cell ALL models with no toxicity against normal human tissue (BJ cells) at the tested concentrations. To develop more potent compounds against ALL and elucidate its potential mode of action, a vitexin-inspired compound library was synthesized. Thus, we developed an improved and scalable protocol for the direct synthesis of 4-quinolone core heterocycles containing an N-sulfonamide using a one-pot condensation reaction protocol. The newly generated compounds represent a novel molecular scaffold against ALL as exemplified by compounds 13 and 15, which demonstrated EC50 values in the low micromolar range (0.3-10 μM) with little to no toxicity in normal cellular models. Computational studies support the hypothesis that these compounds are potential CDK inhibitors. The compounds induced apoptosis, caused cell arrest at G0/G1 and G2/M, and induced ROS in cancer cells.

The natural compound Jatrophone interferes with Wnt/β-catenin signaling and inhibits proliferation and EMT in human triple-negative breast cancer

[This corrects the article DOI: 10.1371/journal.pone.0189864.].