Demonstrating the validity of natural products as anti-infective drugs

This presentation reviews the synthetic or classical development pathway of drug development and contrasts it with developing natural products as drugs. Also presented is an example of a traditional medicine that has been developed from a natural product and has become a "new/old" antiparasitic drug used in the treatment of malaria. The classic paradigm of synthetic drug development breaks down into drug discovery, drug design, preclinical studies, and clinical studies. This paradigm, constructed to weed out failures, results in a drug-development process that is high risk, time consuming, and expensive. The process requires screening an average of 10,000 active compounds to find a single compound that successfully makes its way through validation to drug approval and the marketplace. Following this paradigm, researchers progress from identifying a chemical lead to testing the compound in humans. The World Health Organization (WHO) Guidelines for the Assessment of Herbal Medicines are based on the classical guidelines and follow the classical approach to validating quality, safety, and efficacy--with one major difference. The starting point is to look at the natural product in humans. By taking into account the traditional experience with the product, the validation standard for safety and efficacy of natural products allows for the prolonged and apparently uneventful use of a substance to offer testimony of its safety. The reliance, then, is on experience--or what Western regulatory agencies would call "anecdotal information." Since most phytomedicines are a combination of several active ingredients, the WHO guidelines cover two kinds of combination products: Combinations that are already used in traditional medicine are considered "old" combination products. "New" combination products are well-known substances that are now being used in combination. Artemisia annua, a pervasive weed, has been referred to in Chinese medicine for thousands of years as a treatment for fever. In 1971, an extraction of artemisia yielded activity against Plasmodium berghei, a mouse model for malaria. The isolated compound, artemisinin, is an example of a traditional medicine that started out in humans, but which then provided a lead structure for a standard drug-development paradigm. Today, artemisinin derivatives are being used widely in combination therapy, especially in areas of the world where there is multidrug-resistant malaria.     

DNA topoisomerases as targets for anticancer drugs

DNA topoisomerases are essential enzymes that regulate the conformational changes in DNA topology by catalysing the concerted breakage and rejoining of DNA strands during normal cellular growth. Over the past few years there has been considerable pharmacological interest in these enzymes because inhibitors of DNA topoisomerases represent a major class of anticancer drugs. This review highlights topoisomerase-targeting drugs that have shown promising anticancer activities. The mechanisms by which those drugs interfere with the catalytic cycles of type I and type II DNA topoisomerases and the factors involved in the development of resistance to these drugs are discussed.     

G2 checkpoint abrogators as anticancer drugs

Many conventional anticancer treatments kill cells irrespective of whether they are normal or cancerous, so patients suffer from adverse side effects due to the loss of healthy cells. Anticancer insights derived from cell cycle research has given birth to the idea of cell cycle G2 checkpoint abrogation as a cancer cell specific therapy, based on the discovery that many cancer cells have a defective G1 checkpoint resulting in a dependence on the G2 checkpoint during cell replication. Damaged DNA in humans is detected by sensor proteins (such as hHUS1, hRAD1, hRAD9, hRAD17, and hRAD26) that transmit a signal via ATR to CHK1, or by another sensor complex (that may include gammaH2AX, 53BP1, BRCA1, NBS1, hMRE11, and hRAD50), the signal of which is relayed by ATM to CHK2. Most of the damage signals originated by the sensor complexes for the G2 checkpoint are conducted to CDC25C, the activity of which is modulated by 14-3-3. There are also less extensively explored pathways involving p53, p38, PCNA, HDAC, PP2A, PLK1, WEE1, CDC25B, and CDC25A. This review will examine the available inhibitors of CHK1 (Staurosporin, UCN-01, Go6976, SB-218078, ICP-1, and CEP-3891), both CHK1 and CHK2 (TAT-S216A and debromohymenialdisine), CHK2 (CEP-6367), WEE1 (PD0166285), and PP2A (okadaic acid and fostriecin), as well as the unknown checkpoint inhibitors 13-hydroxy-15-ozoapathin and the isogranulatimides. Among these targets, CHK1 seems to be the most suitable target for therapeutic G2 abrogation to date, although an unexplored target such as 14-3-3 or the strategy of targeting multiple proteins at once may be of interest in the future.     

Target identification of anticancer natural products using a chemical proteomics approach

In recent years, there has been a strong demand worldwide for the identification and development of potential anticancer drugs based on natural products. Natural products have been explored for their diverse biological and therapeutic applications from ancient time. In order to enhance the efficacy and selectivity and to minimize the undesired side effects of anti cancer natural products (ANPs), it is essential to understand their target proteins and their mechanistic pathway. Chemical proteomics is one of the most powerful tools to connect ANP target identification and quantification where labeling and non-labeling based approaches have been used. Herein, we have discussed the various strategies to systemically develop selective ANP based chemical probes to characterise their specific and non-specific target proteins using a chemical proteomic approach in various cancer cell lysates.

Natural products are one of the most effective therapeutic candidates in cancer treatment. In this review, we briefly discuss the target identification of anticancer natural products in different cancer cell lines through a chemical proteomics approach.     

Anthracyclines and ellipticines as DNA-damaging anticancer drugs: recent advances

Over the past forty years, anthracyclines and ellipticines have attracted attention as promising cytostatics. In this review, we focus on their mechanisms of cytoxicity, DNA-damaging effects and adverse side-effects. We also summarize ways to enhance the therapeutic effects of these drugs together with a decrease in their adverse effects. Current drug design strategies are focused on drug bioavailability and their tissue targeting, whereas drug delivery to specific intracellular compartments is rarely addressed. Therefore, therapies utilizing the antineoplastic activities of anthracyclines and ellipticines combined with novel strategies such as nanotechnologies for safer drug delivery, as well as strategies based on gene therapy, could significantly contribute to medical practice.     

Multicomponent domino reactions for the synthesis of biologically active natural products and drugs

A main issue in modern synthetic organic chemistry, which deals with the preparation of natural products, pharmaceuticals, diagnostics, agrochemicals, and other important materials, is the improvement of efficiency, the avoidance of toxic reagents, the reduction of waste, and the responsible treatment of our resources. One of the ways to fulfill these goals is the development and use of domino processes, which consist of several bond-forming reactions and which allow the highly efficient synthesis of complex molecules starting from simple substrates. Herein, the combination of several catalytic bond-forming transformations is clearly most appropriate. The synthesis of the enantiopure alkaloid (-)-hirsutine 22, which has a strong inhibitorial effect on influenza A viruses, was accomplished using a biomimetic domino Knoevenagel-hetero-Diels Alder-solvolysis-hydrogenation process. In a similar way the alkaloids (+)-dihydrocorynantheine 23 and (-)-dihydroantirhine 24 as well as heterosteroids 62, D-homosteroids 65 and 68, and azasteroids 25 are prepared. In addition, novel steroid alkaloids 26 are accessible by a combination of the formation of an iminium salt, a hydride shift, and an alkylation. The anti-leukemic pentacyclic (-)-cephalotaxine 27 is obtained by a combination of two Pd-catalyzed reactions.     

Protein kinases as targets for anticancer agents: from inhibitors to useful drugs

Many components of mitogenic signaling pathways in normal and neoplastic cells have been identified, including the large family of protein kinases, which function as components of signal transduction pathways, playing a central role in diverse biological processes, such as control of cell growth, metabolism, differentiation, and apoptosis. The development of selective protein kinase inhibitors that can block or modulate diseases caused by abnormalities in these signaling pathways is widely considered a promising approach for drug development. Because of their deregulation in human cancers, protein kinases, such as Bcr-Abl, those in the epidermal growth factor-receptor (HER) family, the cell cycle regulating kinases such as the cyclin-dependent kinases, as well as the vascular endothelial growth factor-receptor kinases involved in the neo-vascularization of tumors, are among the protein kinases considered as prime targets for the development of selective inhibitors. These drug-discovery efforts have generated inhibitors and low-molecular weight therapeutics directed against the ATP-binding site of various protein kinases that are in various stages of development (up to Phase II/III clinical trials). Three examples of inhibitors of protein kinases are reviewed, including low-molecular weight compounds targeting the cell cycle kinases; a potent and selective inhibitor of the HER1/HER2 receptor tyrosine kinase, the pyrollopyrimidine PKI166; and the 2-phenyl-aminopyrimidine STI571 (Glivec(R), Gleevec) a targeted drug therapy directed toward Bcr-Abl, the key player in chronic leukemia (CML). Some members of the HER family of receptor tyrosine kinases, in particular HER1 and HER2, have been found to be overexpressed in a variety of human tumors, suggesting that inhibition of HER signaling would be a viable antiproliferative strategy. The pyrrolo-pyrimidine PKI166 was developed as an HER1/HER2 inhibitor with potent in vitro antiproliferative and in vivo antitumor activity. Based upon its clear association with disease, the Bcr-Abl tyrosine kinase in CML represents the ideal target to validate the clinical utility of protein kinase inhibitors as therapeutic agents. In a preclinical model, STI571 (Glivec(R), Gleevec) showed potent in vitro and in vivo antitumor activity that was selective for Abl, c-Kit, and the platelet-derived growth factor-receptor. Phase I/II studies demonstrated that STI571 is well tolerated, and that it showed promising hematological and cytogenetic responses in CML and clinical responses in the c-Kit-driven gastrointestinal tumors.     

恶性肿瘤对抗癌药物的耐药问题

肿瘤化学治疗最大障碍之一是肿瘤细胞对药物的耐受性[1~6]。有些肿瘤,如大肠癌细胞对药物存在固有的抗药性(Intrinsic resistance;consti-tutive resistance)亦称原发性耐药,在治疗开始时就表现出对药物的高度耐受;另一些肿瘤,如乳腺癌、小细胞肺癌、淋巴瘤等,化疗开始时有效,久用则产生抗药,出现获得性抗药性(Acquired resis-tance)亦称继发性耐药[1~4]。原发性耐药和继发性耐药区别是:原发性耐药是未接触药物就已存在的,继发性耐药是接触药物后才产生的。多药耐药性(multidrug resistance,MDR)是肿瘤细胞长期接触某一化疗药物,不仅对此…     

Target-specific mononuclear and binuclear rhenium(i) tricarbonyl complexes as upcoming anticancer drugs

Metal complexes have gradually been attracting interest from researchers worldwide as potential cancer therapeutics. Driven by the many side effects of the popular platinum-based anticancer drug cisplatin, the tireless endeavours of researchers have afforded strategies for the design of appropriate metal complexes with minimal side effects compared to cisplatin and its congeners to limit the unrestricted propagation of cancer. In this regard, transition metal complexes, especially rhenium-based complexes are being identified and highlighted as promising cancer theranostics, which are endowed with the ability to detect and annihilate cancer cells in the body. This is attributed the amazing photophysical properties of rhenium complexes together with their ability to selectively attack different organelles in cancer cells. Therefore, this review presents the properties of different rhenium-based complexes to highlight their recent advances as anticancer agents based on their cytotoxicity results.

In this review, rhenium-based complexes are highlighted as promising cancer theranostics, which are endowed with the ability to detect and annihilate cancer cells in the body.     

Tubulin as a target for anticancer drugs: Agents which interact with the mitotic spindle

Tubulin is the biochemical target for several clinically used anticancer drugs, including paclitaxel and the vinca alkaloids vincristine and vinblastine. This review describes both the natural and synthetic agents which are known to interact with tubulin. Syntheses of the more complex agents are referenced and the potential clinical use of the compounds is discussed. This review describes the biochemistry of tubulin, microtubules, and the mitotic spindle. The agents are discussed in relation to the type of binding site on the protein with which they interact. These are the colchicine, vinca alkaloid, rhizoxin/maytansine, and tubulin sulfhydryl binding sites. Also included are the agents which either bind at other sites or unknown sites on tubulin. The literature is reviewed up to October 1997. © 1998 John Wiley & Sons, Inc., Med Res Rev, 18, No. 4, 259–296, 1998.     

Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA

We developed, synthesized, and tested a multifunctional nanostructured lipid nanocarrier-based system (NLCS) for efficient delivery of an anticancer drug and siRNA directly into the lungs by inhalation. The system contains: (1) nanostructured lipid carriers (NLC); (2) anticancer drug (doxorubicin or paclitaxel); (3) siRNA targeted to MRP1 mRNA as a suppressor of pump drug resistance; (4) siRNA targeted to BCL2 mRNA as a suppressor of nonpump cellular resistance and (5) a modified synthetic analog of luteinizing hormone-releasing hormone (LHRH) as a targeting moiety specific to the receptors that are overexpressed in the plasma membrane of lung cancer cells. The NLCS was tested in vitro using human lung cancer cells and in vivo utilizing mouse orthotopic model of human lung cancer. After inhalation, the proposed NLCS effectively delivered its payload into lung cancer cells leaving healthy lung tissues intact and also significantly decreasing the exposure of healthy organs when compared with intravenous injection. The NLCS showed enhanced antitumor activity when compared with intravenous treatment. The data obtained demonstrated high efficiency of proposed NLCS for tumor-targeted local delivery by inhalation of anticancer drugs and mixture of siRNAs specifically to lung cancer cells and, as a result, efficient suppression of tumor growth and prevention of adverse side effects on healthy organs.