42 Natural Anticancer Products: Classified under the Cancer Hallmarks and the Available Evidence of their Anticancer Activities

About 60% of chemotherapeutic agents used for the treatment of cancer diseases today have been derived from natural products. While some of these agents are identical to the natural molecules found in plants; the others are semisynthetic derivative of the foundational molecule found naturally in the raw sources. Cancers have been reported to express 10 specific hallmark which are used as the key points or steps for targeted therapy against these cancers. Extending the number of these hallmarks to 12 this review article throws light on 44 natural products classifying them according to their target of action. Further, the natural products under consideration are categorized according to the level of evidence present for their anticancer activities.

Technological prospection of anti-inflammatory vanilic acid activity, with emphasis on its semisynthetic derivative Isopropyl Vanilate

Inflammation is the body's response to harmful stimuli such as infections, trauma, or injury. The inflammatory cascade can lead to the development of numerous diseases, and the current drug-therapeutic intervention consists of the use of corticosteroids and non-steroidal anti-inflammatory drugs. However, the use of these is associated with several serious side effects, so it is necessary to search for new alternatives that can minimize this effect. In this prospecting, the objective was to conduct a study on biological activities already described for vanillic acid, with special emphasis on its semi-synthetic derivative of isopropyl vanylate as an anti-inflammatory agent. For this, information was obtained on patent documents based on the INPI, USPTO and EPO databases, using the keywords: vanillic acid, anti-inflammatory agents, isopropyl vanylate, always used in the search field related to the summary of works. As results obtained in the present technological prospection study, it was found that in the international patent databases the documents related to the theme were very scarce and some had a higher number of patents, on vanillic acid, few refer to its anti- inflammatory, and no documents were found on the use of isopropyl vanillate as an anti-inflammatory agent, reinforcing the innovative character of research involving its use in this technology.

Transdermal Buprenorphine- A novel Medication for Postoperative Pain Management Following Abdominal Hysterectomy for Benign Gynecological Conditions

Background: Buprenorphine is a semisynthetic derivative of thebaine which is 75–100 times more potent than morphine and causes less respiratory depression. Efficacy and safety of transdermal buprenorphine have been well established in chronic pain, but data regarding acute postoperative pain relief are still limited. Aim: In this study we compared the efficacy of transdermal buprenorphine patch with injectable tramadol for the relief of postoperative pain (POP) following abdominal hysterectomy for benign gynecological conditions. Settings and design: three-year prospective observational study. Methods and material: One hundred patients undergoing abdominal hysterectomy were allocated to one of two groups. Buprenorphine group: we applied 10 mcg/hr transdermal buprenorphine patch on the lateral upper arm after surgery. The onset of relief from a patch is 8 to 16 hours. So, all patients were given diclofenac suppository 100mg before induction of anesthesia as preemptive analgesic to reduce postoperative pain. Injectable tramadol group : received intramuscular tramadol injections 50mg every 8 hours in the postoperative period. Patients were followed for two days to look for postoperative pain relief and adverse effects. If patients showed a visual analog pain (VAS) score >3, intravenous paracetamol was administered as rescue analgesic. Results: POP was assessed at different time frames: 12, 24, 36 and 48 hours after hysterectomy. Mean pain score at rest, in buprenorphine group was significantly lower than that of the tramadol group. Patients experienced less pain on mobility in the buprenorphine group compared with the tramadol group, which was statistically significant. Conclusion: We concluded that transdermal buprenorphine is an effective and safe alternative to injectable tramadol for providing postoperative analgesia. It provides a higher degree of pain relief, faster postoperative mobilization, lower incidence of postoperative nausea and vomiting and higher satisfaction scores starting 12 hours after surgery. However, for the first 12 post-operative hours, there is need for additional analgesia.

A Fluoro Derivative of Embelin, as Potent B-RAF Inhibitor in Melanoma

Background: Melanoma is one of the common forms of skin cancer and B-RAF is a mutated protein found in most Melanomas. The important function of B-RAF is normal cell growth and survival. Most of known B-RAF mutations are V600E mutations. Vemurafenib is the currently used fluorine based drug used for V600E mutations but this drug has side effects, so in this scenario, more potent drugs with less side effects are required. Objective: This study aims to develop a more effective lead compound as B-RAF inhibitor from a hydroxyquinone, by structural modification of embelin, a naturally occurring hydroxybenzoquinone, which has got a potency of detoxifying blood, hence useful in wide range of skin diseases. Thus a fluorine substituted semisynthetic derivative of embelin, 5-(3-chloro-4-trifluoromethoxy phenyl amino)-2- hydroxy-3-undecyl- [1, 4] benzoquinone to fight against skin cancer was prepared. Method: Fluoro derivative of embelin was synthesized by the direct condensation of embelin with 3-chloro-4-trifluoromethoxy aniline. The structure of the product was characterized using various spectral data, obtained from IR, 1H NMR, 19F NMR, 13C NMR and Mass spectrum. Various in vitro studies like Antiproliferative study in A375 Cell Lines, (B-RAF Elisa), Western Blotting analysis, Gene Expression study by Reverse Transcriptase PCR, Caspase assay, Flow Cytometry analysis, Clonogenic assay and Transwell Migration assay were carried out to find its biological activity. Results: A semisynthetic derivative of embelin 5-(3-chloro-4-trifluoromethoxy phenyl amino)-2-hydroxy-3-undecyl- [1, 4] benzoquinone (EOCF) was prepared and the structure of the derivative was confirmed by spectral analysis. The MTT assay proves that the fluoro derivative of embelin exhibited better anticancer activity in Melanoma cell lines than the parent compound, embelin. Western blot analysis showed that B-RAF expression level was reduced by the addition of derivative than the parent compound embelin. The Caspase ELISA analysis indicated that the derivative was found to be a good apoptotic marker and from the flow cytometry analysis, it was observed that the cell arrest occurs at G0/G1 phase. Its antimetastatic activity determined using Clonogenic assay indicated that the derivative, EOCF inhibits the metastatic effects in melanoma cell lines. Migratory potential of Melanoma cells were significantly reduced in presence of EOCF when Transwell migration assay was conducted. Conclusion: This work established that the potency of the synthesized compound was more than the parent compound, embelin when it was structurally modified with 3-chloro-4-trifluoromethoxy aniline and that the derivative can be used as a lead molecule for further drug discovery.

Tigecycline: pharmacological concerns and resistance

Tigecycline, a semisynthetic derivative of minocycline, has a broad spectrum of activity against both gram positive and gram negative multidrug resistant bacteria. The drug acts on 30S ribosomal subunit and inhibits protein synthesis. Since the drug has excellent tissue distribution, it is very useful for treatment of skin infections, intra-abdominal infections and pneumonia. Side effects of the drug are usually mild. The common side effects include nausea and vomiting. The exact mechanism of resistance remains unclear. However, resistance mediated by enhanced expression of resistance nodulation cell division (RND) type efflux pumps is one of the most frequently reported mechanisms. Resistance has been observed worldwide. However, the rate of resistance is low.

Evaluation of Microbial Transformation of 10-deoxoartemisinin by UPLC-ESI-Q-TOF-MSE

10-deoxoartemisinin is a semisynthetic derivative of artemisinin that lacks a lactone carbonyl group at the 10-position, and has stronger antimalarial properties than artemisinin. However, 10-deoxoartemisinin has limited utility as a therapeutic agent because of its low solubility and bioavailability. Hydroxylated 10-deoxoartemisinins are a series of properties-improved derivatives. Via microbial transformation, which can hydroxylate 10-deoxoartemisinin at multiple sites, the biotransformation products of 10-deoxoartemisinin have been investigated in this paper. Using ultra-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MSE) combined with UNIFI software, products of microbial transformation of 10-deoxoartemisinin were rapidly and directly analyzed. The hydroxylation abilities of nine microorganisms were compared using this method. All of the microorganisms evaluated were able to hydroxylate 10-deoxoartemisinin, and a total of 35 hydroxylated products were identified. These can be grouped into dihydroxylated 10-deoxoartemisinins, monohydroxylated 10-deoxoartemisinins, hydroxylated dehydrogenated 10-deoxoartemisinins, and hydroxylated hydrogenated 10-deoxoartemisinins. Cunninghamella echinulata and Cunninghamella blakesleeana are able to hydroxylate 10-deoxoartemisinin, and their biotransformation products are investigated here for the first time. Cunninghamella elegans CICC 40250 was shown to most efficiently hydroxylate 10-deoxoartemisinin, and could serve as a model organism for microbial transformation. This method could be used to generate additional hydroxylated 10-deoxoartemisinins for further research.

Microbiology and Preclinical Review of Omadacycline

Omadacycline is a novel aminomethylcycline antimicrobial and semisynthetic derivative of tetracycline. In vitro, omadacycline displays potent activity against gram-positive and many gram-negative bacteria, including methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, β-hemolytic streptococci, vancomycin-resistant Enterococcus, and Enterobacteriaceae. Omadacycline is also active against atypical and anaerobic pathogens, including Legionella pneumophila, Mycoplasma spp., Ureaplasma spp., Bacteroides spp., and Clostridioides difficile. This review outlines the microbiology and preclinical studies of omadacycline, including its mechanism of action; spectrum of activity; protein binding; activity in the presence of surfactant, serum, normal, and pH-adjusted urine, or bacterial biofilms; postantibiotic effect; pharmacodynamic properties; and in vitro and in vivo efficacy. The results of in vitro and in vivo animal studies support the observations made in phase III clinical trials and the clinical development of omadacycline.