C1,C2-ether derivatives of the Amaryllidaceae alkaloid lycorine: Retention of activity of highly lipophilic analogues against cancer cells

As a continuation of the studies aimed at the development of new anticancer agents derived from the Amaryllidaceae alkaloid lycorine, 35 C1,C2-ether analogues of this natural product were synthesized. The compounds were evaluated for antiproliferative activities in vitro in a panel of tumor cell lines with varied levels of apoptosis resistance. A strong correlation between the compound lipophilicity and anticancer activity was observed, indicating that cell permeability properties must be an important determinant in the design of lycorine-based anticancer agents. A theoretical docking model, consistent with the experimental observations, is presented.     

Synthetic analogues of the montanine-type alkaloids with activity against apoptosis-resistant cancer cells

In a search of small molecules active against apoptosis-resistant cancer cells, a skeletal rearrangement of alkaloid haemanthamine was utilized to generate a series of compounds possessing the alkaloid montanine ring system. The synthesized compounds were found to inhibit proliferation of cancer cells resistant to apoptosis at micromolar concentrations. Selected compounds were also active against patient-derived glioblastoma cells expressing stem-cell markers. This is the first report describing the preparation of synthetic analogues of the montanine-type alkaloids with antiproliferative activity. The compounds prepared in the current investigation appear to be a useful starting point for the development of agents to fight cancers with apoptosis resistance, and thus, associated with poor prognoses.     

Identification of natural compounds tubercidin and lycorine HCl against small‐cell lung cancer and BCAT1 as a therapeutic target

Although small‐cell lung cancer (SCLC) accounts for a small fraction of lung cancer cases (~15%), the prognosis of patients with SCLC is poor with an average overall survival period of a few months without treatment. Current treatments include standard chemotherapy, which has minimal efficacy and a newly developed immunotherapy that thus far, benefits a limited number of patients. In the current study, we screened a natural product library and identified 5 natural compounds, in particular tubercidin and lycorine HCl, that display prominent anti‐SCLC activities in vitro and in vivo. Subsequent RNA‐sequencing and functional validation assays revealed the anti‐SCLC mechanisms of these new compounds, and further identified new cellular factors such as BCAT1 as a potential therapeutic target with clinical implication in SCLC patients. Taken together, our study provides promising new directions for fighting this aggressive lung cancer.     

Further experiments on structure-activity relationships among the lycorine alkaloids

Synthetic lycorine analogues, five Amaryllidaceae alkaloids and narciclasine, all structurally related to lycorine, were tested for their ability to inhibit ascorbic acid biosynthesis in vivo. The highest potency observed was displayed by narciclasine followed by compounds having an aromatic C-ring. Derivatives modified at C-1 and/or C-2 were inactive, while the compound with a double bond between these positions is a weak inhibitor. Also lutessine and its deacetyl derivative having an α-methoxyl group bonded to C-4 of the D-ring appeared completely inactive. These results confirm that the presence of an appropriately substituted C-ring is a necessary requirement for optimal ‘response-triggering’ contact between the lycorine derivatives and the specific receptor. Functional groups jutting out from the α-side of the molecule do not allow a good fit with the binding sites.     

Evaluation of HIV-1 inhibition by stereoisomers and analogues of the sesquiterpenoid hydroquinone peyssonol A

Peyssonol A, a brominated natural product with documented anti-HIV-1 activity, was synthesized racemically along with 6 isomers and 15 truncated analogues and synthetic precursors. These compounds were screened in a cell-based assay against a recombinant HIV-1 strain to investigate structure–activity relationships. The results obtained suggest that both the aliphatic and aromatic domains of peyssonol A are responsible for its potency, while the stereochemical configuration of the substituents on the aliphatic domain, including their bromine atom, are largely irrelevant. Although none of the analogues tested were as potent as the parent natural product, several exhibited greater therapeutic indices due to reduced cytotoxicity, noting that nearly all compounds tested were measurably cytotoxic.     

Synthesis of furanone-based natural product analogues with quorum sensing antagonist activity

The synthesis of 5- and 3-(1'-hydroxyalkyl)-substituted 5H-furan-2-ones 4a-d and 8a-d as well as 5-alkylidene-5H-furan-2-ones 5a-d is described. A study of the structure-activity relationship of these furanone-based natural product analogues towards two different quorum sensing systems is reported. Although the synthesized compounds are not as potent quorum sensing inhibitors as some natural counterparts and a synthetic analogue hereof, interesting structure-activity relationships are seen.     

Semisynthetic neoboutomellerone derivatives as ubiquitin-proteasome pathway inhibitors

The interesting pharmacological properties of neoboutomellerones 1 and 2 were the basis for the assembly of a small library of analogues consisting of natural products isolated from the plant Neoboutonia melleri and of semisynthetic derivatives. As the two enone systems (C23-C24a and C1-C3) and the two hydroxyls groups (C22 and C26) of neoboutomellerones are required for activity, modifications were focused on these functional groups. Biological evaluation by using a cellular assay for proteasome activity provided clues regarding the mechanism of action of these natural products and synthetic derivatives. Certain neoboutomellerone derivatives inhibited the proliferation of human WM-266-4 melanoma tumor cells at submicromolar concentration and warrant evaluation as anticancer agents.     

Various sensitivities of yeasts to lycorine

Lycorine, an Amaryllidaceae alkaloid, is a powerful inhibitor of growth in higher plants and algae. Thirty-one strains of yeasts, belonging to different genera and species, were screened to study the effect of lycorine on their growth. The strains were incubated at 25 degrees C in a 2% glucose medium with different concentrations of lycorine (10, 50 and 100 microM), and their growth after 72 hours was evaluated. Most of the strains showed no sensitivity to lycorine. However, in Schizosaccharomyces pombe (IMAT-V Pbx) and Aureobasidium pullulans (DBV A77) lycorine significantly inhibited growth (59-73%), while, on the contrary, in Saccharomycopsis fibuligera (DBV 3812) and Cryptococcus terreus (CBS 1895) it was clearly stimulated (76-140%). The fact that lycorine inhibits growth in some yeasts while it stimulates it in others means that neither of the two previously formulated interpretations on the molecular mechanism of action of alkaloid can explain all cases. In other words, it does not seem that lycorine just inhibits protein synthesis, as claimed by Kukhanova et al. (1983), nor, on the other hand, do the data presented here prove that lycorine specifically inhibits ascorbic acid biosynthesis (Arrigoni et al., 1975). We must now check the ability of yeasts to split lycorine and study whether yeasts do actually have an ascorbic acid system.     

Cytotoxic activities of Amaryllidaceae alkaloids against gastrointestinal cancer cells

The treatment of many diseases is highly dependent on natural products and natural products can also be used as design templates for future anticancer drugs. Thirteen Amaryllidaceae alkaloids possessing α-crinane, β-crinane, galantamine, lycorine and tazettine-type skeleton have been isolated in our laboratory, and their cytotoxicity against p53-mutated gastrointestinal cancer cells were evaluated. At the same time, healthy small intestine cells were used to determine overall toxicity against noncancerous cells. In this study, we demonstrated that haemanthamine, haemanthidine and lycorine showed strong cytotoxicity against p53-mutated Caco-2 and HT-29 colorectal adenocarcinoma cells as quantified in terms of IC₅₀ values. We for the first time observed approximately 20 times higher IC₅₀values against normal intestine epithelial cells FHs-74 Int after haemanthamine and lycorine treatment when compared with Caco-2 and HT-29 cancer cells. In conclusion, our data indicate that α-C2 bridged haemanthamine may be perspective anticancer drug candidate for further semisynthetic modification and structure-activity relationship study.     

The potential role of anibamine, a natural product CCR5 antagonist, and its analogues as leads toward development of anti-ovarian cancer agents

Chemokines and their receptors play important roles in the development of primary tumors and their metastases. Particularly CC chemokine receptor 5 (CCR5) and its ligand CC chemokine ligand 5 (CCL5/RANTES) seem to be critical in proliferation and invasion of ovarian cancer, the leading cause of death from gynecological malignancies in the United States. Anibamine, the first natural product CCR5 antagonist, and its analogues were examined for their effects on proliferation of the OVCAR-3 ovarian cancer cells in order to validate their candidacy as leads to develop novel anti-ovarian cancer agents. Acting as CCR5 antagonists, anibamine and its analogues significantly suppressed CCL5-induced intracellular Ca(2+) flux. The compounds also inhibited the proliferation of OVCAR-3 at micromolar to submicromolar range. Moreover, anibamine and several analogues did not show significant cytotoxicity in NIH 3T3 cells at concentrations up to 20μM. Based on these results, anibamine and one of its synthetic analogues were defined as potential leads to develop novel agents against ovarian cancer.     

Structure-activity studies on the lycorine pharmacophore: A potent inducer of apoptosis in human leukemia cells

The direct chemoselective differential functionalization of the ring-C hydroxyl groups present in the Amaryllidaceae alkaloid lycorine is described allowing for selective manipulation of the 1,2-hydroxyl groups. A mini-library comprised of synthetic and natural lycorane alkaloids was prepared and their apoptosis-inducing activity investigated in human leukemia (Jurkat) cells. Further insights into the nature of this interesting apoptosis-inducing pharmacophore are described, including the requirement of both free hydroxyl groups in ring-C.     

Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation

Selective clearance of senescent cells (SCs) has emerged as a potential therapeutic approach for age-related diseases, as well as chemotherapy- and radiotherapy-induced adverse effects. Through a cell-based phenotypic screening approach, we recently identified piperlongumine (PL), a dietary natural product, as a novel senolytic agent, referring to small molecules that can selectively kill SCs over normal or non-senescent cells. In an effort to establish the structure-senolytic activity relationships of PL analogues, we performed a series of structural modifications on the trimethoxyphenyl and the α,β-unsaturated δ-valerolactam rings of PL. We show that modifications on the trimethoxyphenyl ring are well tolerated, while the Michael acceptor on the lactam ring is critical for the senolytic activity. Replacing the endocyclic C2–C3 olefin with an exocyclic methylene at C2 render PL analogues 47–49 with increased senolytic activity. These α-methylene containing analogues are also more potent than PL in inducing ROS production in WI-38 SCs. Similar to PL, 47–49 reduce the protein levels of oxidation resistance 1 (OXR1), an important oxidative stress response protein that regulates the expression of a variety of antioxidant enzymes, in cells. This study represents a useful starting point toward the discovery of senolytic agents for therapeutic uses.     

Synthesis and in vitro evaluation of analogues of avocado-produced toxin (+)-(R)-persin in human breast cancer cells

A structure-activity study of several new synthetic analogues of the avocado-produced toxin persin has been conducted, with compounds being evaluated for their cytostatic and pro-apoptotic effects in human breast cancer cells. A 4-pyridinyl derivative demonstrated activity comparable to that of the natural product, suggesting future directions for exploration of structure-activity relationships.     

石蒜碱药理活性及构效关系研究进展

石蒜碱是药用石蒜科植物的有效成分之一,是重要的异喹啉类生物碱.石蒜碱拥有刚性的环系骨架、连续的手性中心、三级胺等独特的化学结构特征.同时其药理活性丰富多样,近年来,针对其抗癌、抗病毒、抗炎、抗寄生虫、抑制乙酰胆碱酯酶活性的研究越来越多,尤其在抗癌、抗病毒方面石蒜碱表现出较大潜力,特别是新型冠状病毒SARS-CoV-2研...     

Synthesis and antiplasmodial activity of lycorine derivatives

Twenty seven lycorine derivatives were prepared and evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum. The best antiplasmodial activities were achieved with lycorine derivatives that present free hydroxyl groups at C-1 and C-2 or esterified as acetates or isobutyrates. The double bond C-2–C-3 is also important for the activity. Concerning to the antiplasmodial activity of the secolycorines, the higher values were obtained with the replacement of the methylenedioxy moiety by hydroxyl or acetate groups and with methyl substituent attached to the nitrogen atom.     

Novel Acyclic Derivatives of Aica-Riboside (1-(β-D-Ribopuranosyl)5-Amino-4-Imidazolecarboxamide), Potential Antiviral Agents

Abstract

A synthetic approach is described to obtain from AICA-riboside acyclic analogues of 2′-deoxyribosides in which the C(2′)-C(3′) bond is cleaved and the natural configuration (E) at the anomeric C (1′)-position is retained.     

Synthesis,cytotoxic activity and structure–activity relationships of hedychenone analogues

Hedychenone, a plant-derived labdane diterpenoid, showed potent in vitro cytotoxic activity against cancerous cells. In the present study, a series of analogues have been synthesized by modification of the furanoid ring, double bond and the vinylic methyl functionality of this natural product lead and evaluated for their cytotoxic activities against human cancer cell lines. The structures of the target compounds were established by IR, ¹H NMR and mass spectral analysis. Majority of the analogues displayed potent activity than the parent compound, hedychenone. Preliminary structure–activity relationship studies indicated that furanoid ring has a greater impact on cytotoxicity than that of the decalone nucleus. However, dimerization through C-8 significantly enhanced the cytotoxic activity of the hedychenone.     

Synthesis and biological evaluation of B-ring analogues of (-)-rhazinilam

Three macrocyclic analogues of rhazinilam 1 having a 11- or 12-membered B-ring with an endocyclic carbamate group or an amino-acid residue were synthesized from the natural product. These analogues 3 and 4 displayed a very low activity on tubulin. Thirty N-1 and C-16 substituted analogues of rhazinilam were also synthesized regioselectively from rhazinilam. Stereochemical analyses showed that N-1 and C-16alpha analogues have the same conformation as rhazinilam, whereas C-16beta analogues adopt a different conformation for rings B and D. All N-1 and C-16 analogues were less active than rhazinilam on tubulin, though analogues 5a, 6aalpha, 6balpha, and 6f having the less bulky substituents retained close affinities. A few analogues either active (like 6f) or inactive (like 5o) on tubulin showed significant inhibition of the growth of KB cancer cells.     

Anticancer activity of synthetic analogues of the phorboxazoles

The phorboxazoles are recently described natural products that are extremely cytostatic towards the National Cancer Institute's panel of 60 tumor cell lines. We report here the results of preliminary structure-activity studies of synthetic analogues of the phorboxazoles against BT-20 breast cancer, NALM-6 B-lineage ALL, U373 brain tumor, and U373 glioblastoma cell lines. These data indicate the importance of several of the natural products' structural moieties for potent anticancer activity.