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      Plant-Derived Anticancer Compounds as New Perspectives in Drug Discovery and Alternative Therapy

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          Abstract

          Despite the recent advances in the field of chemically synthetized pharmaceutical agents, nature remains the main supplier of bioactive molecules. The research of natural products is a valuable approach for the discovery and development of novel biologically active compounds possessing unique structures and mechanisms of action. Although their use belongs to the traditional treatment regimes, plant-derived compounds still cover a large portion of the current-day pharmaceutical agents. Their medical importance is well recognized in the field of oncology, especially as an alternative to the limitations of conventional chemotherapy (severe side effects and inefficacy due to the occurrence of multi-drug resistance). This review offers a comprehensive perspective of the first blockbuster chemotherapeutic agents of natural origin’s (e.g. taxol, vincristine, doxorubicin) mechanism of action using 3D representation. In addition is portrayed the step-by-step evolution from preclinical to clinical evaluation of the most recently studied natural compounds with potent antitumor activity (e.g. resveratrol, curcumin, betulinic acid, etc.) in terms of anticancer mechanisms of action and the possible indications as chemotherapeutic or chemopreventive agents and sensitizers. Finally, this review describes several efficient platforms for the encapsulation and targeted delivery of natural compounds in cancer treatment

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          Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019

          This review is an updated and expanded version of the five prior reviews that were published in this journal in 1997, 2003, 2007, 2012, and 2016. For all approved therapeutic agents, the time frame has been extended to cover the almost 39 years from the first of January 1981 to the 30th of September 2019 for all diseases worldwide and from ∼1946 (earliest so far identified) to the 30th of September 2019 for all approved antitumor drugs worldwide. As in earlier reviews, only the first approval of any drug is counted, irrespective of how many "biosimilars" or added approvals were subsequently identified. As in the 2012 and 2016 reviews, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions, and the designation "natural product botanical", or "NB", to cover those botanical "defined mixtures" now recognized as drug entities by the FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or synthetic variations using their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from 1946 to 1980, of the 75 small molecules, 40, or 53.3%, are N or ND. In the 1981 to date time frame the equivalent figures for the N* compounds of the 185 small molecules are 62, or 33.5%, though to these can be added the 58 S* and S*/NMs, bringing the figure to 64.9%. In other areas, the influence of natural product structures is quite marked with, as expected from prior information, the anti-infective area being dependent on natural products and their structures, though as can be seen in the review there are still disease areas (shown in Table 2) for which there are no drugs derived from natural products. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are still able to identify only two de novo combinatorial compounds (one of which is a little speculative) approved as drugs in this 39-year time frame, though there is also one drug that was developed using the "fragment-binding methodology" and approved in 2012. We have also added a discussion of candidate drug entities currently in clinical trials as "warheads" and some very interesting preliminary reports on sources of novel antibiotics from Nature due to the absolute requirement for new agents to combat plasmid-borne resistance genes now in the general populace. We continue to draw the attention of readers to the recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated"; thus we consider that this area of natural product research should be expanded significantly.
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            A view on drug resistance in cancer

            The problem of resistance to therapy in cancer is multifaceted. Here we take a reductionist approach to define and separate the key determinants of drug resistance, which include tumour burden and growth kinetics; tumour heterogeneity; physical barriers; the immune system and the microenvironment; undruggable cancer drivers; and the many consequences of applying therapeutic pressures. We propose four general solutions to drug resistance that are based on earlier detection of tumours permitting cancer interception; adaptive monitoring during therapy; the addition of novel drugs and improved pharmacological principles that result in deeper responses; and the identification of cancer cell dependencies by high-throughput synthetic lethality screens, integration of clinico-genomic data and computational modelling. These different approaches could eventually be synthesized for each tumour at any decision point and used to inform the choice of therapy.
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              Discovery and resupply of pharmacologically active plant-derived natural products: A review

              Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                19 February 2021
                February 2021
                : 26
                : 4
                : 1109
                Affiliations
                [1 ]Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timisoara, Romania; cadehelean@ 123456umft.ro (C.A.D.); iasmina.marcovici@ 123456umft.ro (I.M.); dorinacoricovac@ 123456umft.ro (D.C.); iuliapinzaru@ 123456umft.ro (I.P.)
                [2 ] Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timisoara, Romania
                [3 ]“Victor Babeș” University of Medicine and Pharmacy Timisoara, Faculty of Medicine, Eftimie Murgu Square No. 2, RO-300041 Timisoara, Romania; siurciuc@ 123456umft.ro (S.I.); tavi@ 123456octaviancretu.ro (O.M.C.)
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-5760-8872
                https://orcid.org/0000-0003-2295-1926
                Article
                molecules-26-01109
                10.3390/molecules26041109
                7922180
                33669817
                883eacf9-209b-4d83-a1b9-acec6656d22d
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 01 February 2021
                : 16 February 2021
                Categories
                Review

                bioactive compounds,doxorubicin, paclitaxel, vincristine, resveratrol, curcumin, rutin, betulinic acid, antitumoral effect,chemoprevention

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