Naphthylisoquinoline alkaloids: novel agents against the causative pathogens of eumycetoma and actinomycetoma-en route to broad-spectrum antimycetomal drugs.

Mycetoma is a devastating neglected tropical infection of the subcutaneous tissues. It is caused by fungal and bacterial pathogens recognized as eumycetoma and actinomycetoma, respectively. Mycetoma treatment involves diagnosing the causative microorganism as a prerequisite to prescribing a proper medication. Current therapy of fungal eumycetoma causative agents, such as Madurella mycetomatis, consists of long-term antifungal medication with itraconazole followed by surgery, yet with usually unsatisfactory clinical outcomes. Actinomycetoma, on the contrary, usually responds to treatment with co-trimoxazole and amikacin. Therefore, there is a pressing need to discover novel broad-spectrum antimicrobial agents to circumvent the time-consuming and costly diagnosis. Using the resazurin assay, a series of 23 naphthylisoquinoline (NIQ) alkaloids and related naphthoquinones were subjected to in vitro screening against two fungal strains of M. mycetomatis and three bacterial strains of Actinomadura madurae and A. syzygii. Seven NIQs, mostly dimers, showed promising in vitro activities against at least one strain of the mycetoma-causative pathogens, while the naphthoquinones did not show any activity. A synthetic NIQ dimer, 8,8'''-O,O-dimethylmichellamine A (18), inhibited all tested fungal and bacterial strains (IC50 = 2.81-12.07 µg/mL). One of the dimeric NIQs, michellamine B (14), inhibited a strain of M. mycetomatis and significantly enhanced the survival rate of Galleria mellonella larvae infected with M. mycetomatis at concentrations of 1 and 4 µg/mL, without being toxic to the uninfected larvae. As a result, broad-spectrum dimeric NIQs like 14 and 18 with antimicrobial activity are considered hit compounds that could be worth further optimization to develop novel lead antimycetomal agents.

Discovery, Biosynthetic Origin, and Heterologous Production of Massinidine, an Antiplasmodial Alkaloid.

Bacteria of the genus Massilia represent an underexplored source of bioactive natural products. Here, we report the discovery of massinidine (1), a guanidine alkaloid with antiplasmodial activity, from these microbes. The unusual scaffold of massinidine is shown to originate from l-phenylalanine, acetate, and l-arginine. Massinidine biosynthesis genes were identified in the native producer and validated through heterologous expression in Myxococcus xanthus. Bioinformatic analyses indicate that the potential for massinidine biosynthesis is distributed in various proteobacteria.

Dimeric naphthylisoquinoline alkaloids: polyketide-derived axially chiral bioactive quateraryls.

Covering: up to April 2019Dimeric naphthylisoquinoline (NIQ) alkaloids are an emerging group of structurally, biosynthetically, and pharmacologically intriguing natural products, as yet isolated from African and Asian lianas belonging to the genus Ancistrocladus Wall. (Ancistrocladaceae) exclusively. These metabolites and their monomers are the only known di- and tetrahydroisoquinoline alkaloids that do not originate from aromatic amino acids, but from polyketide precursors. Stereochemically, dimeric NIQs are characterized by the presence of several stereogenic centers and up to three consecutive chiral axes. The most recent highlight is the discovery of dimers that witness a new biosynthetic follow-up chemistry: by oxidative cyclization, leading to bridged, cage-like molecular architectures. Depending on their individual structures, the dimers show promising biological activities, including antiviral, antiprotozoal, and antitumor properties, most of them quite different from those of the monomers. This is the first review on these multi-facetted dimeric alkaloids, dealing with their isolation, their structural diversity, their biosynthetic origin, their pharmacological properties, and their total synthesis.

Ancistrolikokine E3, a 5,8'-Coupled Naphthylisoquinoline Alkaloid, Eliminates the Tolerance of Cancer Cells to Nutrition Starvation by Inhibition of the Akt/mTOR/Autophagy Signaling Pathway.

PANC-1 human pancreatic cancer cells are characterized by their ability to proliferate aggressively under hypovascular and hypoxic conditions in the tumor microenvironment, displaying a remarkable tolerance to nutrition starvation. The antiausterity strategy is a new approach in anticancer drug discovery aiming at the identification of potent agents that inhibit preferentially the survival of tumor cells during a limited supply of nutrients and oxygen. The new 5,8'-coupled naphthyldihydroisoquinoline alkaloid ancistrolikokine E3 (4), isolated from the Congolese liana Ancistrocladus likoko, showed potent preferential cytotoxicity against PANC-1 cells under nutrient-deprived conditions, with a PC50 value of 2.5 µM, without exhibiting toxicity in normal, nutrient-rich medium. The compound was found to induce dramatic alterations in cell morphology, leading to cell death. Moreover, it inhibited significantly PANC-1 cell migration and colony formation in a concentration-dependent manner. This study on 4 provides the first live evidence of the effect of a naphthyldihydroisoquinoline alkaloid against PANC-1 cells in nutrient-deprived medium. Mechanistic investigations conducted suggest that compound 4 is a potent inhibitor of the activation of the Akt/mTOR pathway. Furthermore, it inhibited the expression levels of the key autophagy regulators Atg5, Atg12, Beclin-1, LC3-I, and LC3-II. The results demonstrated that ancistrolikokine E3 (4) is a potent early-stage inhibitor of the autophagy pathway in PANC-1 human pancreatic cancer cells. Ancistrolikokine E3 (4) and related naphthylisoquinoline alkaloids are promising potential lead compounds for anticancer drug development based on the antiausterity strategy.

Ancistroyafungines A-D, 5,8'- and 5,1'-coupled naphthylisoquinoline alkaloids from a Congolese Ancistrocladus species, with antiausterity activities against human PANC-1 pancreatic cancer cells.

Four new naphthylisoquinoline alkaloids, the 5,8'-coupled ancistroyafungines A-C (1-3) and the 5,1'-linked ancistroyafungine D (4), have been isolated from the stem bark of an as yet unidentified Ancistrocladus (Ancistrocladaceae) liana recently discovered near the village Yafunga, in the North-Central region of the Democratic Republic of the Congo. Likewise obtained were eleven analogs previously identified in related African and Asian Ancistrocladus species, exhibiting five different coupling types, viz., 5,8', 5,1', 7,1', N,6', and N,8'. All of the alkaloids are S-configured at C-3 and possess an oxygen function at C-6 in the isoquinoline portion, and, thus, belong to the subclass of "Ancistrocladaceae-type" alkaloids. This finding is geo- and chemotaxonomically remarkable, since - apart from one other Ancistrocladus species from the Central Congo Basin - only Southeast Asian and East African Ancistrocladaceae are known to exclusively produce naphthylisoquinolines with these structural features. Moreover, the alkaloid pattern of this Congolese liana clearly demarcates this plant from all other Ancistrocladus taxa that have so far been botanically described, which suggests that it might represent a new species or subspecies. The new ancistroyafungines display strong preferential cytotoxic activities towards human PANC-1 pancreatic cancer cells in nutrient-deprived medium, without showing toxicity in normal, nutrient-rich conditions.

Michellamines A6 and A7, and further mono- and dimeric naphthylisoquinoline alkaloids from a Congolese Ancistrocladus liana and their antiausterity activities against pancreatic cancer cells.

Michellamines A6 (1) and A7 (2) are the first dimers of 5,8'-coupled naphthylisoquinoline alkaloids with cis-configured stereocenters in both tetrahydroisoquinoline subunits. They were isolated from the leaves of a recently discovered, yet unidentified Congolese Ancistrocladus liana that shares some morphological characteristics with Ancistrocladus likoko. Two further new dimeric analogs, michellamines B4 (3) and B5 (4), were obtained, along with two previously likewise unknown monomers, ancistrobonsolines A1 (5) and A2 (6), which, besides one single known other example, are the only naphthyldihydroisoquinolines with an M-configured biaryl axis and R-configuration at C-3. Moreover, five compounds earlier reported from other Ancistrocladus species were identified, ancistroealaine C (7), korupensamines A (8a) and B (8b), and michellamines A2 (9) and E (10). Their complete structural elucidation succeeded due to the fruitful interplay of spectroscopic, chemical, and chiroptical methods. Chemotaxonomically, the stereostructures of the metabolites clearly delineate this Congolese Ancistrocladus liana from all known related species, showing that it might be a new taxon. Ancistrobonsolines A1 (5) and A2 (6) exhibited strong preferential cytotoxicities against human PANC-1 pancreatic cancer cells under nutrient-deprived conditions, without displaying toxicity in normal, nutrient-rich medium. Against cervical HeLa cancer cells, the dimeric alkaloids michellamines A6 (1) and E (10) displayed the highest cytotoxic activities, comparable to that of the standard agent, 5-fluorouracil. Furthermore, ancistrobonsolines A1 (5) and A2 (6) showed weak-to-moderate antiprotozoal activities.