Natural products as leads to potential mosquitocides

Mosquitoes are the crucial vectors for a number of mosquito-borne infectious diseases i.e. dengue, yellow fever, chikungunya, malaria, Rift Valley fever, elephantiasis, Japanese Encephalitis, and Murray Valley encephalitis etc. Besides, they also transmit numerous arboviruses (arthropod-borne viruses) for example West Nile virus, Saint Louis encephalitis virus, Eastern equine encephalomyelitis virus, Everglades virus, Highlands J virus, and La Crosse Encephalitis virus. The emergence of widespread insecticide resistance and the potential environmental issues associated with some synthetic insecticides (such as DDT) has indicated that additional approaches to control the proliferation of mosquito population would be an urgent priority research. The present review highlights some natural product mosquitocides that are target-specific, biodegradable, environmentally safe, and botanicals in origin.     

Microbial natural products: molecular blueprints for antitumor drugs

Microbes from two of the three domains of life, the Prokarya, and Eukarya, continue to serve as rich sources of structurally complex chemical scaffolds that have proven to be essential for the development of anticancer therapeutics. This review describes only a handful of exemplary natural products and their derivatives as well as those that have served as elegant blueprints for the development of novel synthetic structures that are either currently in use or in clinical or preclinical trials together with some of their earlier analogs in some cases whose failure to proceed aided in the derivation of later compounds. In every case, a microbe has been either identified as the producer of secondary metabolites or speculated to be involved in the production via symbiotic associations. Finally, rapidly evolving next-generation sequencing technologies have led to the increasing availability of microbial genomes. Relevant examples of genome mining and genetic manipulation are discussed, demonstrating that we have only barely scratched the surface with regards to harnessing the potential of microbes as sources of new pharmaceutical leads/agents or biological probes.     

Telomerase inhibitors as novel antitumor drugs

Telomerase activity is detected in most types of human tumors, but it is almost undetectable in normal somatic cells; therefore, telomerase is a promising therapeutic target. The present review describes various approaches to telomerase inhibition, namely, antisense therapy, RNA interference, and the use of ribozymes and agents interacting with the telomeric G-quadruplex. The use of these compounds in clinical research is analyzed in the review.     

Natural products: A continuing source of novel drug leads

Background

Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chemistry (late 1980s), shifted the focus of drug discovery efforts from Nature to the laboratory bench.

Scope of Review

This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases. It is clear Nature will continue to be a major source of new structural leads, and effective drug development depends on multidisciplinary collaborations.

Major Conclusions

The explosion of genetic information led not only to novel screens, but the genetic techniques permitted the implementation of combinatorial biosynthetic technology and genome mining. The knowledge gained has allowed unknown molecules to be identified. These novel bioactive structures can be optimized by using combinatorial chemistry generating new drug candidates for many diseases.

General Significance

The advent of genetic techniques that permitted the isolation / expression of biosynthetic cassettes from microbes may well be the new frontier for natural products lead discovery. It is now apparent that biodiversity may be much greater in those organisms. The numbers of potential species involved in the microbial world are many orders of magnitude greater than those of plants and multi-celled animals. Coupling these numbers to the number of currently unexpressed biosynthetic clusters now identified (> 10 per species) the potential of microbial diversity remains essentially untapped.     

Polyacrylates of noble metals as potential antitumor drugs

The antitumor activity of polyacrylates of the noble metals containing argentum (argacryl), aurum (auracryl) and platinum (platacryl) has been studied using experimental murine solid tumor models (Lewis lung carcinoma and Acatol adenocarcinoma). It has been found that polyacrylates of the noble metals are capable of inhibiting tumor development by 50–90% compared to control. Auracryl that inhibits the growth of Lewis lung carcinoma and Acatol adenocarcinoma by 80 and 90%, respectively, compared to control is the most efficient among the tested compounds and can be recommended for the further profound preclinical studies.     

Natural products as a screening resource

Natural products have been the most productive source of leads for new drugs, but they are currently out of fashion with the pharmaceutical industry. New approaches to sourcing novel compounds from untapped areas of biodiversity coupled with the technical advances in analytical techniques (such as microcoil NMR and linked LC-MS-NMR) have removed many of the difficulties in using natural products in screening campaigns. As the 'chemical space' occupied by natural products is both more varied and more drug-like than that of combinatorial chemical collections, synthetic and biosynthetic methods are being developed to produce screening libraries of natural product-like compounds. A renaissance of drug discovery inspired by natural products can be predicted.     

Topoisomerase-targeting antitumor drugs

Much has been learned about the unusual type of DNA damage produced by the topoisomerases. The mechanism by which these lesions trigger cell death, however, remains unclear, but it appears that DNA metabolic machinery transforms reversible single-strand cleavable complexes to overt strand breaks which may be an initial event in the cytotoxic pathway. For the topoisomerase I poisons, they produce breaks at replication forks that appear to be the equivalent of a break in duplex DNA. Indicating that this may be an important cytotoxic lesion is the hypersensitivity to camptothecin of the yeast mutant rad52, which is deficient in double-strand-break-repair. The topoisomerase poisons preferentially kill proliferating cells. In the case of the topoisomerase I poison camptothecin, dramatic S-phase-specific cytotoxicity can explain its preferential action on proliferating cells. For the topoisomerase II poisons, high levels of the enzyme in proliferating cells, and very low levels in quiescent cells appear to explain the resistance of quiescent cells to the drug's cytotoxic effects. Thus, the topoisomerase poisons convert essential enzymes into intracellular, proliferating-cell toxins. The identification of both topoisomerase I and II as the specific targets of cancer chemotherapeutic drugs now provides a rational basis for the development of topoisomerase I poisons for possible clinical use. Knowledge of the molecular mechanisms of cell killing may lead to the identification of new therapies for treating cancer. The topoisomerase poisons appear to be a good tool for studying cell killing mechanisms as they produce highly specific and reversible lesions.     

Atp-bound topoisomerase ii as a target for antitumor drugs

Topoisomerase II (TOP2) poisons interfere with the breakage/reunion reaction of TOP2 resulting in DNA cleavage. In the current studies, we show that two different classes (ATP-sensitive and -insensitive) of TOP2 poisons can be identified based on their differential sensitivity to the ATP-bound conformation of TOP2. First, in the presence of 1 mm ATP or the nonhydrolyzable analog adenosine 5'-(beta,gamma-imino)triphosphate, TOP2-mediated DNA cleavage induced by ATP-sensitive TOP2 poisons (e.g. doxorubicin, etoposide, mitoxantrone, and 4'-(9-acridinylamino)methanesulfon-m-anisidide) was 30-100-fold stimulated, whereas DNA cleavage induced by ATP-insensitive TOP2 poisons (e.g. amonafide, batracylin, and menadione) was only slightly (less than 3-fold) affected. In addition, ADP was shown to strongly antagonize TOP2-mediated DNA cleavage induced by ATP-sensitive but not ATP-insensitive TOP2 poisons. Second, C427A mutant human TOP2alpha, which exhibits reduced ATPase activity, was shown to exhibit cross-resistance to all ATP-sensitive but not ATP-insensitive TOP2 poisons. Third, using ciprofloxacin competition assay, TOP2-mediated DNA cleavage induced by ATP-sensitive but not ATP-insensitive poisons was shown to be antagonized by ciprofloxacin. These results suggest that ATP-bound TOP2 may be the specific target of ATP-sensitive TOP2 poisons. Using Lac repressor-operator complexes as roadblocks, we show that ATP-bound TOP2 acts as a circular clamp capable of entering DNA ends and sliding on unobstructed duplex DNA.     

Methotrexate gamma-hydroxamate derivatives as potential dual target antitumor drugs

A series of new aminopteroyl-based hydroxamate derivatives were synthesized and tested in vitro in cell culture models as potential dual target drugs. These compounds were designed to target two families of enzymes, matrix metalloproteinases (MMP) and a folate enzyme, dihydrofolate reductase (DHFR). These enzymes are the components of two unrelated cellular pathways and they are often over-expressed in metastasizing tumors. In addition to the synthesis and full structural characterization of the hybrid molecules, we describe their inhibitory activities against a series of MMPs (MMP-2, MMP-7, MMP-9, MMP-14) and DHFR, as well as their antiproliferative activity in three cancer cell lines. The new hydroxamate derivatives of MTX proved to be effective inhibitors of MMPs and DHFR in the micromolar and nanomolar range, respectively. Furthermore, they showed strong antiproliferative activity against A549 cells (non-small cell lung carcinoma), and PPC-1 and Tsu-Pr1 prostate cancer cell lines. Therefore, based on the present results, these bi-functional drugs may be good candidates to target specific tumors in animal models due to potential combined effects on two pathways crucial for tumor development.     

Sarcomelicope alkaloids as leads for the discovery of new antitumor acronycine derivatives

The acridone alkaloid acronycine first isolated from Acronychia baueri Schott (Rutaceae) in 1948, was later shown to exhibit a promising activity against a broad spectrum of solid tumors. Nevertheless, clinical trials only gave poor results, probably due to the moderate potency and low water solubility of this alkaloid. Early studies on structure-activity relationships in the series concluded that the 1,2-double bond was an essential structural requirement to observe cytotoxic activity. It is the reason why the isolation in our laboratory of the unstable acronycine epoxide from several New-Caledonian Sarcomelicope species led to the hypothesis of bioactivation of acronycine by transformation of the 1,2-double bond into the corresponding oxirane in vivo. Consequently, there was interest in the search for acronycine derivatives modified in the pyran ring and having improved stability, but a similar reactivity toward nucleophilic agents as acronycine epoxide. Accordingly, we synthesized a series of cis- and trans-1,2-dihydroxy-1,2-dihydroacronycine diesters which exhibited interesting antitumor properties with a broadened spectrum of activity and increased potency when compared with acronycine. (±)-Cis-1,2-diacetoxy-1,2-dihydroacronycine was of particular interest, due to its marked activity in vivo against the resistant solid tumor C 38 colon carcinoma. The demonstration that acronycine should interact with DNA by some noncovalent process able to stabilize the double helix against thermal denaturation prompted us to develop benzo[b]acronycine analogues possessing an additional aromatic ring linearly fused on the natural alkaloid basic skeleton. When tested against a panel of cancer cell lines in vitro, cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diesters exhibited cytotoxic activities within the same range of potency as the most active drugs currently used in cancer chemotherapy. In vivo, cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine (S23906-1), selected for further preclinical development, demonstated a marked antitumor activity in human orthotopic models of lung, ovarian and colon cancers xenografted in nude mice. This revised version was published online in June 2006 with corrections to the Cover Date.     

Natural antibodies as contaminants of hybridoma products

This report cites an example of natural antibodies in mouse serum and ascites fluid which may contaminate hybridoma products and cause difficulties in interpreting their reactions. These natural antibodies react with determinants expressed on human foetal glycoproteins (extracted from meconium) and on other blood group precursor-like substances which express a number of tumour associated- and differentiation antigens. Variable amounts of these antibodies may be present in the ascites fluid of mice obtained by intraperitoneal injection of cloned hydridomas. Although in most cases the hybridoma antibodies will be used at dilutions beyond the endpoint of these contaminating antibodies, it is important to be aware of possible reactions due to natural and acquired antibodies with diverse specificities in evaluating the reactions of hybridoma products harvested from any type of serum containing medium.     

Natural products as probes in pharmaceutical research

From the start of the pharmaceutical research natural products played a key role in drug discovery and development. Over time many discoveries of fundamental new biology were triggered by the unique biological activity of natural products. Unprecedented chemical structures, novel chemotypes, often pave the way to investigate new biology and to explore new pathways and targets. This review summarizes the recent results in the area with a focus on research done in the laboratories of Novartis Institutes for BioMedical Research. We aim to put the technological advances in target identification techniques in the context to the current revival of phenotypic screening and the increasingly complex biological questions related to drug discovery.     

New natural products as new leads for antibacterial drug discovery

Natural products have been a rich source of antibacterial drugs for many decades, but investments in this area have declined over the past two decades. The purpose of this review article is to provide a recent survey of new natural product classes and the mechanisms by which they work.     

Natural product based leads to fight against leishmaniasis

The growing incidence of parasitic resistance against generic pentavalent antimonials, specifically for visceral disease in Indian subcontinent, is a serious issue in Leishmania control. Notwithstanding the two treatment alternatives, that is amphotericin B and miltefosine are being effectively used but their high cost and therapeutic complications limit their use in endemic areas. In the absence of a vaccine candidate, identification, and characterization of novel drugs and targets is a major requirement of leishmanial research. This review describes current drug regimens, putative drug targets, numerous natural products that have shown promising antileishmanial activity alongwith some key issues and strategies for future research to control leishmaniasis worldwide.     

Natural products of commercial potential as medicines.

Recent advances in research on natural products (of both low and high molecular weight) of plant origin and their commercial potential as medicines are discussed. Substances with immunomodulating, antiviral, antimicrobial, antiparasite, antitumor, anti-inflammatory, hypoglycemic, tranquillizer and antifeedant activities are focused on.     

New antitumor leads from a peptidomimetic library

A parallel combinatorial library of over 1600 compounds has been designed and synthesized for the development of new potential peptidomimetic protein tyrosine kinase (PTK) inhibitor leads. These peptidomimetic molecules are aimed at intervening with the substrate binding site of the pp60^c-src enzyme. The new structures were based on known PTK inhibitors with at least two variously substituted aromatic moieties attached by spacer groups of different length and flexibility. Eleven bis-aryl-type inhibitory compounds were found in the range of 18–100 μM IC₅₀ concentrations from combinations of 12 different substituents. Molecular modeling of the active compounds showed a characteristic distance of 12–14 Å between the farthest sp² carbon atoms of the two aromatic rings. Conformational analysis of several peptide substrates recently found for pp60^c-src PTK showed that the energy-minimized conformers had the same distance between the two aromatic moieties. Several compounds in the library not only showed remarkable PTK inhibitory activity but also a significant apoptosis-inducing effect on HT-29 human colon tumor cells.     

New antitumor leads from a peptidomimetic library

A parallel combinatorial library of over 1600 compounds has been designed and synthesized for the development of new potential peptidomimetic protein tyrosine kinase (PTK) inhibitor leads. These peptidomimetic molecules are aimed at intervening with the substrate binding site of the pp60^c-src enzyme. The new structures were based on known PTK inhibitors with at least two variously substituted aromatic moieties attached by spacer groups of different length and flexibility. Eleven bis-aryl-type inhibitory compounds were found in the range of 18–100 M IC₅₀ concentrations from combinations of 12 different substituents. Molecular modeling of the active compounds showed a characteristic distance of 12–14 Å between the farthest sp² carbon atoms of the two aromatic rings. Conformational analysis of several peptide substrates recently found for pp60^c-src PTK showed that the energy-minimized conformers had the same distance between the two aromatic moieties. Several compounds in the library not only showed remarkable PTK inhibitory activity but also a significant apoptosis-inducing effect on HT-29 human colon tumor cells.     

Sulfur-containing marine natural products as leads for drug discovery and development

Among the large series of marine natural products (MNPs), sulfur-containing MNPs have emerged as potential therapeutic agents for the treatment of a range of diseases. Herein, we reviewed 95 new sulfur-containing MNPs isolated during the period between 2021 and March 2023. In addition, we discuss that the widely used strategies and the emerging technologies including natural product-based antibody drug conjugates (ADCs), small-molecule-based proteolysis targeting chimeras (PROTACs), nanotechnology-based drug carriers, artificial intelligence (AI)-driven drug discovery have been used for improving the efficiency and success rate of NP-based drug development. We also provide perspectives regarding the challenges and opportunities in sulfur-containing MNPs based drug discovery and development and future research directions.