The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers

Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications and can be found in household items, including foods, cosmetics, and cleaning supplies. Over the past three decades, it has also been investigated for its potential anticancer activity. Clinical trials with an oral POH formulation administered to cancer patients failed to realize therapeutic expectations, although an intra-nasal POH formulation yielded encouraging results in malignant glioma patients. Based on its amphipathic nature, POH revealed the ability to overcome biological barriers, primarily the blood–brain barrier (BBB), but also the cytoplasmic membrane and the skin, which appear to be characteristics that critically contribute to POH’s value for drug development and delivery. In this review, we present the physicochemical properties of POH that underlie its ability to overcome the obstacles placed by different types of biological barriers and consequently shape its multifaceted promise for cancer therapy and applications in drug development. We summarized and appraised the great variety of preclinical and clinical studies that investigated the use of POH for intranasal delivery and nose-to-brain drug transport, its intra-arterial delivery for BBB opening, and its permeation-enhancing function in hybrid molecules, where POH is combined with or conjugated to other therapeutic pharmacologic agents, yielding new chemical entities with novel mechanisms of action and applications.

Download Full-text

Endogenous Biomarkers for SLC Transporter-Mediated Drug-Drug Interaction Evaluation

Molecules ◽

10.3390/molecules26185500 ◽

2021 ◽

Vol 26 (18) ◽

pp. 5500

Author(s):

Yang Li ◽

Zahra Talebi ◽

Xihui Chen ◽

Alex Sparreboom ◽

Shuiying Hu

Keyword(s):

Drug Development ◽

Drug Transport ◽

Development Process ◽

Membrane Transporters ◽

Drug Candidates ◽

Endogenous Substrates ◽

Slc Transporter ◽

Preclinical And Clinical Studies ◽

Uptake Transporters ◽

Early Phases

Membrane transporters play an important role in the absorption, distribution, metabolism, and excretion of xenobiotic substrates, as well as endogenous compounds. The evaluation of transporter-mediated drug-drug interactions (DDIs) is an important consideration during the drug development process and can guide the safe use of polypharmacy regimens in clinical practice. In recent years, several endogenous substrates of drug transporters have been identified as potential biomarkers for predicting changes in drug transport function and the potential for DDIs associated with drug candidates in early phases of drug development. These biomarker-driven investigations have been applied in both preclinical and clinical studies and proposed as a predictive strategy that can be supplanted in order to conduct prospective DDIs trials. Here we provide an overview of this rapidly emerging field, with particular emphasis on endogenous biomarkers recently proposed for clinically relevant uptake transporters.

Download Full-text

NMR Assisted Antimicrobial Peptide Designing: Structure Based Modifications and Functional Correlation of a Designed Peptide VG16KRKP

Current Medicinal Chemistry ◽

10.2174/0929867326666190624090817 ◽

2020 ◽

Vol 27 (9) ◽

pp. 1387-1404 ◽

Cited By ~ 2

Author(s):

Karishma Biswas ◽

Humaira Ilyas ◽

Aritreyee Datta ◽

Anirban Bhunia

Keyword(s):

Antimicrobial Agents ◽

Biological Properties ◽

Structure Characterization ◽

Drug Resistant ◽

Functional Correlation ◽

Naturally Occurring ◽

High Resolution Nmr ◽

Different Types ◽

Reduced Activity ◽

Poor Stability

Antimicrobial Peptides (AMPs), within their realm incorporate a diverse group of structurally and functionally varied peptides, playing crucial roles in innate immunity. Over the last few decades, the field of AMP has seen a huge upsurge, mainly owing to the generation of the so-called drug resistant ‘superbugs’ as well as limitations associated with the existing antimicrobial agents. Due to their resilient biological properties, AMPs can very well form the sustainable alternative for nextgeneration therapeutic agents. Certain drawbacks associated with existing AMPs are, however, issues of major concern, circumventing which are imperative. These limitations mainly include proteolytic cleavage and hence poor stability inside the biological systems, reduced activity due to inadequate interaction with the microbial membrane, and ineffectiveness because of inappropriate delivery among others. In this context, the application of naturally occurring AMPs as an efficient prototype for generating various synthetic and designed counterparts has evolved as a new avenue in peptide-based therapy. Such designing approaches help to overcome the drawbacks of the parent AMPs while retaining the inherent activity. In this review, we summarize some of the basic NMR structure based approaches and techniques which aid in improving the activity of AMPs, using the example of a 16-residue dengue virus fusion protein derived peptide, VG16KRKP. Using first principle based designing technique and high resolution NMR-based structure characterization we validate different types of modifications of VG16KRKP, highlighting key motifs, which optimize its activity. The approaches and designing techniques presented can support our peers in their drug development work.

Download Full-text

Lights and Shadows in Immuno-Oncology Drug Development

Cancers ◽

10.3390/cancers13040691 ◽

2021 ◽

Vol 13 (4) ◽

pp. 691

Author(s):

Milana Bergamino Sirvén ◽

Sonia Pernas ◽

Maggie C. U. Cheang

Keyword(s):

Drug Development ◽

Checkpoint Inhibitors ◽

Late Phase ◽

New Drugs ◽

Successful Outcome ◽

Different Types ◽

Cancer Types ◽

Clinical Trial Designs ◽

Oncology Drug Development ◽

Critical Aspects

The rapidly evolving landscape of immuno-oncology (IO) is redefining the treatment of a number of cancer types. IO treatments are becoming increasingly complex, with different types of drugs emerging beyond checkpoint inhibitors. However, many of the new drugs either do not progress from phase I-II clinical trials or even fail in late-phase trials. We have identified at least five areas in the development of promising IO treatments that should be redefined for more efficient designs and accelerated approvals. Here we review those critical aspects of IO drug development that could be optimized for more successful outcome rates in all cancer types. It is important to focus our efforts on the mechanisms of action, types of response and adverse events of these novel agents. The use of appropriate clinical trial designs with robust biomarkers of response and surrogate endpoints will undoubtedly facilitate the development and subsequent approval of these drugs. Further research is also needed to establish biomarker-driven strategies to select which patients may benefit from immunotherapy and identify potential mechanisms of resistance.

Download Full-text

Effects of some Amino-acid and Purine Antagonists on Chick Embryos

Development ◽

10.1242/dev.6.2.365 ◽

1958 ◽

Vol 6 (2) ◽

pp. 365-372

Author(s):

C. H. Waddington ◽

Margaret Perry

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Effective Concentration ◽

Metabolic Inhibitors ◽

Chick Embryos ◽

Purine Analogue ◽

Know How ◽

Naturally Occurring ◽

Different Types ◽

Strong Action

Several authors have studied the effects on developing embryos of substances which are analogues of naturally occurring amino-acids and purines, and known to act, in other systems, as metabolic inhibitors. It was emphasized by Waddington, Feldman, & Perry (1955) that any particular substance may exhibit very different effects in embryos of different types. They found, for instance, that the purine analogue 8-azaguanine has a very strong action in the chick and a much lesser one in the newt embryo. It is therefore necessary to consider the various classes of embryos separately. In this communication we shall be concerned only with chick embryos. Substances under test can be administered to such embryos by injection through the shell, as was done in the paper cited above With this technique it is impossible to know how much diffusion takes place of the substance injected, and one cannot therefore be certain of the effective concentration which actually reaches the embryo.

Download Full-text

Current Update on Preclinical and Clinical Studies of Resveratrol, a Naturally Occurring Phenolic Compound

Critical Reviews in Eukaryotic Gene Expression ◽

10.1615/critreveukaryotgeneexpr.2019027836 ◽

2019 ◽

Vol 29 (6) ◽

pp. 529-537 ◽

Cited By ~ 3

Author(s):

Vijaya Paul Samuel ◽

Gaurav Gupta ◽

Rajiv Dahiya ◽

Dev Anand Jain ◽

Anurag Mishra ◽

...

Keyword(s):

Phenolic Compound ◽

Clinical Studies ◽

Naturally Occurring ◽

Preclinical And Clinical Studies

Download Full-text

Cheminformatics techniques in antimalarial drug discovery and development from natural products 1: basic concepts

Physical Sciences Reviews ◽

10.1515/psr-2018-0130 ◽

2019 ◽

Vol 4 (7) ◽

Author(s):

Samuel Egieyeh ◽

Sarel F. Malan ◽

Alan Christoffels

Keyword(s):

Natural Products ◽

Drug Development ◽

Antimalarial Drug ◽

Drug Discovery And Development ◽

Drug Candidates ◽

Structure Activity ◽

Preclinical And Clinical Studies ◽

Research Cost

Abstract A large number of natural products, especially those used in ethnomedicine of malaria, have shown varying in vitro antiplasmodial activities. Facilitating antimalarial drug development from this wealth of natural products is an imperative and laudable mission to pursue. However, limited manpower, high research cost coupled with high failure rate during preclinical and clinical studies might militate against the pursuit of this mission. These limitations may be overcome with cheminformatic techniques. Cheminformatics involves the organization, integration, curation, standardization, simulation, mining and transformation of pharmacology data (compounds and bioactivity) into knowledge that can drive rational and viable drug development decisions. This chapter will review the application of cheminformatics techniques (including molecular diversity analysis, quantitative-structure activity/property relationships and Machine learning) to natural products with in vitro and in vivo antiplasmodial activities in order to facilitate their development into antimalarial drug candidates and design of new potential antimalarial compounds.

Download Full-text

Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery

Molecules ◽

10.3390/molecules25133066 ◽

2020 ◽

Vol 25 (13) ◽

pp. 3066 ◽

Cited By ~ 1

Author(s):

Francesca Seghetti ◽

Rita Maria Concetta Di Martino ◽

Elena Catanzaro ◽

Alessandra Bisi ◽

Silvia Gobbi ◽

...

Keyword(s):

Drug Resistance ◽

Lymphoblastic Leukemia ◽

Leukemia Cell ◽

Drug Candidate ◽

Mitochondrial Apoptosis ◽

Lead Compound ◽

Anticancer Effect ◽

Hybrid Molecules ◽

New Chemical Entities ◽

Peculiar Behavior

The burden of neoplastic diseases is widely recognized as a severe cause of mortality. The clinical inadequacy of most anticancer therapeutics urgently prompted intense drug discovery efforts toward the identification of new chemical entities endowed with a potent and safe antitumor profile. In this scenario, targeting cancer cells apoptosis machinery has emerged as a relevant strategy, useful for tackling the emergence of drug resistance. On this basis, a small library of naturally inspired hybrid molecules was obtained by combining, through a click chemistry approach, “privileged” synthons such as curcumin scaffold and 1,2,3-triazole building block. Compound 1, bearing a para-fluoro phenyl moiety, showed low-micromolar potency against T acute lymphoblastic leukemia cell growth. More in-depth biologic studies demonstrated, for this analog, cell death-inducing properties associated with its capability to simultaneously activate both the receptor and the mitochondrial apoptosis cascades. This peculiar behavior offers promises for achieving an expanded anticancer effect, namely intense cytotoxic response coupled with reduced predisposition of chemoresistance insurgence. Altogether, this study allowed the identification of compound 1 as a lead compound worth to be progressed as an anticancer drug candidate.

Download Full-text

Clinical, Pathological, and Ethical Considerations for the Conduct of Clinical Trials in Dogs with Naturally Occurring Cancer: A Comparative Approach to Accelerate Translational Drug Development

ILAR Journal ◽

10.1093/ilar/ily019 ◽

2018 ◽

Vol 59 (1) ◽

pp. 99-110 ◽

Cited By ~ 5

Author(s):

Daniel Regan ◽

Kelly Garcia ◽

Douglas Thamm

Keyword(s):

Clinical Trials ◽

Drug Development ◽

Translational Research ◽

Cancer Biology ◽

Comparative Approach ◽

Cancer Drug ◽

Comparative Oncology ◽

Pet Dogs ◽

Naturally Occurring

Abstract The role of comparative oncology in translational research is receiving increasing attention from drug developers and the greater biomedical research community. Pet dogs with spontaneous cancer are important and underutilized translational models, owing to dogs’ large size and relative outbreeding, combined with their high incidence of certain tumor histotypes with significant biological, genetic, and histological similarities to their human tumor counterparts. Dogs with spontaneous tumors naturally develop therapy resistance and spontaneous metastasis, all in the context of an intact immune system. These fundamental features of cancer biology are often lacking in induced or genetically engineered preclinical tumor models and likely contribute to their poor predictive value and the associated overall high failure rate in oncology drug development. Thus, the conduct of clinical trials in pet dogs with naturally occurring cancer represents a viable surrogate and valuable intermediary step that should be increasingly incorporated into the cancer drug discovery and development pipeline. The development of molecular-targeted therapies has resulted in an expanded role of the pathologist in human oncology trials, and similarly the expertise of veterinary pathologists will be increasingly valuable to all phases of comparative oncology trial design and conduct. In this review, we provide a framework of clinical, ethical, and pathology-focused considerations for the increasing integration of translational research investigations in dogs with spontaneous cancer as a means to accelerate clinical cancer discovery and drug development.

Download Full-text

Effect of Metallic Poisons. Especially Manganese, on Aging of Vulcanized Natural Rubber

Rubber Chemistry and Technology ◽

10.5254/1.3543309 ◽

1947 ◽

Vol 20 (3) ◽

pp. 821-826

Keyword(s):

Organic Acids ◽

Natural Rubber ◽

Harmful Effect ◽

Manganese Compound ◽

Naturally Occurring ◽

Different Types ◽

Salts Of Organic Acids ◽

General Experience ◽

Manganese Compounds ◽

Harmful Effects

Abstract 1. Information received from rubber manufacturers on their experience of the effects of manganese and copper on aging is summarized. Although there is evidence that the amounts of these impurities in fillers tended to increase during the early war years (1939–42), it seems to be the general experience that little trouble arose from their effects on the properties of the rubber. Fillers containing as much as 0.05–0.10 per cent of manganese, or 0.005 per cent of copper, have not shown any obvious harmful effects. 2. Experiments with a large number of manganese compounds, including naturally occurring (mineral) forms and salts of organic acids, used in amounts equivalent to 0.01 per cent manganese on the raw rubber, have failed to show any pronounced harmful effect on the aging (oven or oxygen bomb) of a vulcanized natural rubber containing mercaptobenzothiazole, although deterioration was noticeably accelerated in some cases. Probably on account of the smallness of the effects observed, it is not possible as yet to draw any conclusion as to the relative activities of different types of manganese compound. 3. According to results of previous workers, manganese in the amount used in the present experiments can produce a more serious effect than these experiments indicate. The effect of manganese is known to depend on the type of mix used, and this aspect of the problem would thus appear to merit further investigation, as does also the influence of the method and degree of dispersion of the manganese compound in the rubber mix.

Download Full-text

Mycorrhizae of Abies concolor in California

Canadian Journal of Botany ◽

10.1139/b77-156 ◽

1977 ◽

Vol 55 (10) ◽

pp. 1345-1350 ◽

Cited By ~ 3

Author(s):

Isabel F. Alvarez ◽

Fields W. Cobb Jr.

Keyword(s):

Sierra Nevada ◽

Mycorrhizal Fungi ◽

Abies Concolor ◽

North Central ◽

Chemical Reagents ◽

The North ◽

Naturally Occurring ◽

White Fir ◽

Different Types ◽

Cenococcum Graniforme

Nine different types of mycorrhizae were observed on naturally occurring white fir seedlings in the north central Sierra Nevada, including one formed by the ubiquitous Cenococcum graniforme. The macro- and micro-scopic characteristics and reactions to different chemical reagents are described for five types. Possible mycorrhizal fungi of white fir are listed. Nursery-grown seedlings examined were ectomycorrhizal; intracellular penetration was not observed. None of the naturally occurring mycorrhizal types were found on nursery seedlings.

Download Full-text