Rational approaches, design strategies, structure activity relationship and mechanistic insights for anticancer hybrids (original) (raw)
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Concept of Hybrid Drugs and Recent Advancements in Anticancer Hybrids
Pharmaceuticals, 2022
Cancer is a complex disease, and its treatment is a big challenge, with variable efficacy of conventional anticancer drugs. A two-drug cocktail hybrid approach is a potential strategy in recent drug discovery that involves the combination of two drug pharmacophores into a single molecule. The hybrid molecule acts through distinct modes of action on several targets at a given time with more efficacy and less susceptibility to resistance. Thus, there is a huge scope for using hybrid compounds to tackle the present difficulties in cancer medicine. Recent work has applied this technique to uncover some interesting molecules with substantial anticancer properties. In this study, we report data on numerous promising hybrid anti-proliferative/anti-tumor agents developed over the previous 10 years (2011-2021). It includes quinazoline, indole, carbazole, pyrimidine, quinoline, quinone, imidazole, selenium, platinum, hydroxamic acid, ferrocene, curcumin, triazole, benzimidazole, isatin, pyrrolo benzodiazepine (PBD), chalcone, coumarin, nitrogen mustard, pyrazole, and pyridine-based anticancer hybrids produced via molecular hybridization techniques. Overall, this review offers a clear indication of the potential benefits of merging pharmacophoric subunits from multiple different known chemical prototypes to produce more potent and precise hybrid compounds. This provides valuable knowledge for researchers working on complex diseases such as cancer.
Dalton Transactions, 2013
Chemotherapeutic agents combining several active groups within a single molecule can modulate multiple cellular pathways and, thus, exhibit higher efficacy than single-target drugs. In this study, six new hybrid compounds combining tamoxifen (TAM) or ferrocifen (FcTAM) structural motifs with suberoylanilide hydroxamic acid (SAHA) were synthesised and evaluated. Antiproliferative activity was first explored in cancer cell lines. Combining FcTAM and SAHA structural motifs to form the unprecedented FcTAM-SAHA hybrid molecule led to an increased cytotoxicity (IC 50 = 0.7 μM) in triple-negative MDA-MB-231 breast cancer cells when compared to FcTAM or SAHA alone (IC 50 = 2.6 μM and 3.6 μM, respectively), while the organic hybrid analogue TAM-SAHA was far less cytotoxic (IC 50 = 8.6 μM). In hormone-dependent MCF-7 breast cancer cells, FcTAM-SAHA was more active (IC 50 = 2.0 μM) than FcTAM (IC 50 = 4.4 μM) and TAM-SAHA (IC 50 > 10 μM), but less toxic than SAHA (IC 50 = 1.0 μM). Surprisingly, FcTAM-PSA, an N 1 -phenylsuberamide derivative, also possessed strong antiproliferative activity (IC 50 = 0.5 μM and 1.8 μM in MDA-MB-231 and MCF-7 cells, respectively). Subsequent biochemical studies indicate that estrogen receptor alpha (ERα) and histone deacetylases (HDAC) are not the main targets of the hybrid compounds for their antiproliferative effect. Interestingly, both organometallic compounds were able to induce p21 waf1/cip1 gene expression in MCF-7 breast cancer cells in accordance with their antiproliferative activity.
Design and synthesis of hybrid compounds as novel drugs and medicines
RSC Advances, 2022
The development of highly effective conjugate chemistry approaches is a way to improve the quality of drugs and of medicines. The aim of this paper is to highlight and review such hybrid compounds and the strategies underpinning their design. A variety of unique hybrid compounds provide an excellent toolkit for novel biological activity, e.g. anticancer and non-viral gene therapy (NVGT), and as templates for killing bacteria and preventing antibiotic drug resistance. First we discuss the anticancer potential of hybrid compounds, containing daunorubicin, benzyl-or tetrahydroisoquinoline-coumarin, and cytotoxic NSAID-pyrrolizidine/ indolizine hybrids, then NVGT cationic lipid-based delivery agents, where steroids or long chain fatty acids as the lipid moiety are bound to polyamines as the cationic moiety. These polyamines can be linear as in spermidine or spermine, or on a polycyclic sugar template, aminoglycosides kanamycin and neomycin B, the latter substituted with six amino groups. They are highly efficient for the delivery of both fluorescent DNA and siRNA. Molecular precedents can be found for the design of hybrid compounds in the natural world, e.g., squalamine, the first representative of a previously unknown class of natural antibiotics of animal origin. These polyamine-bile acid (e.g. cholic acid type) conjugates display many exciting biological activities with the bile acids acting as a lipidic region and spermidine as the polycationic region. Analogues of squalamine can act as vectors in NVGT. Their natural role is as antibiotics. Novel antibacterial materials are urgently needed as recalcitrant bacterial infection is a worldwide problem for human health. Ribosome inhibitors founded upon dimers of tobramycin or neomycin, bound as ethers by a 1,6-hexyl linker or a more complex diether-disulfide linker, improved upon the antibiotic activity of aminoglycoside monomers by 20-to 1200-fold. Other hybrids, linked by click chemistry, conjugated ciprofloxacin to neomycin, trimethoprim, or tedizolid, which is now in clinical trials.
Framework of medicinal chemistry to enhance rational design of Anti-Cancer activity
BULLETIN OF ENVIRONMENT, PHARMACOLOGY AND LIFE SCIENCES, 2022
Organic-inorganic hybrid frames which have been hybridization polysaccharides consisting of metal ions or groups and organic linkers are amongst the most recent classes of nanomaterials studied for chemotherapy application. Gas/vapor segregation, gas storage, catalytic, luminous nanomaterials, including biological photography are just a few of the uses for MOFs. These nanostructures have special characteristics that make them suitable for use as prodrugs in biomedicine. First, because of their porous structure, they are harmless, reversible, & capable of carrying significant factor loading of the anti-neoplastic chemical. Nanoparticles also have a well-defined crystalline phase which can be described using various methodological approaches, plus their dimensions are appropriate for controlling the release of drugs in vivo.CD-MOF-1 and CD-MOF-2, two highly uncommon b-cyclodextrin assisted metal-organic structures (MOFs), were crystallized for the first time using a framework method. The CD-MOFs were utilized to conduct controlled release and toxicity experiments, which demonstrated their good biological properties as therapeutic applications.
Oncology Reports, 2020
One of the most commonly discussed topics in the field of drug discovery is the continuous search for anticancer therapies, in which small-molecule development plays an important role. Although a number of techniques have been established over the past decades, one of the main methods for drug discovery and development is still represented by rational, ligand-based drug design. However, the success rate of this method could be higher if not affected by cognitive bias, which renders many potential druggable scaffolds and structures overlooked. The present study aimed to counter this bias by presenting an objective overview of the most important heterocyclic structures in the development of anti-proliferative drugs. As such, the present study analyzed data for 91,438 compounds extracted from the Developmental Therapeutics Program (DTP) database provided by the National Cancer Institute. Growth inhibition data from these compounds tested on a panel of 60 cancer cell lines representing various tissue types (NCI-60 panel) was statistically interpreted using 6 generated scores assessing activity, selectivity, growth inhibition efficacy and potency of different structural scaffolds, Bemis-Murcko skeletons, chemical features and structures common among the analyzed compounds. Of the most commonly used rings, the most prominent anti-proliferative effects were produced by quinoline, tetrahydropyran, benzimidazole and pyrazole, while overall, the optimal results were produced by complex ring structures that originate from natural compounds. These results highlight the impact of certain ring structures on the anti-proliferative effects in drug design. In addition, considering that medicinal chemists usually focus their research on simpler scaffolds the majority of the time with no significant pay-off, the present study indicates several unused complex scaffolds that could be exploited when designing anticancer therapies for optimal results in the fight against cancer.
2018
In an attempt to design and synthesize a new class of anticancer molecules, we have reported coupling of aryl aldehyde, ptoluidine and morpholine based isocyanide with cyclopropane carboxylic acid to generate a small library of 08 compounds (5a-5h) by ugi multicomponent reaction in a single step manner. Structures of the newly synthesized compounds were recognized on the basis of spectral data i.e. 1H NMR, 13C NMR, IR and Mass. These compounds were screened for their anticancer activity against nine basic panels as well as NCI-60 cell-lines. In vitro anticancer studies revealed that the compound 5a showed maximum potency against HCT-116 in colon cancer cell lines with GI50 values 46.27 μg/ml.
Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?
Molecules
Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers’ molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compl...
Design Synthesis and Evaluation of Novel Anticancer Agents
2017
Structure and downstream signaling of EGFR 2.3 EGFR over expression in various carcinomas 2.4 EGFR TK mutations and resistance 2.5 EGFR targeted therapies 2.6 Rationale for EGFR TK as target 2.7 Conclusion AIMS AND OBJECTIVES 3.1 Need for newer anticancer agents 3.2 Objectives of the study SYNTHESIS AND CHARACTERIZATION 4.1 4-(benzyloxy)phenyl](4-phenylpiperazin-1-yl)methanone derivatives 4.2 4-(3-(4-methylpiperazin-1-yl)propoxy)-N-phenylbenzamide (scaffold-II) and (4-(3-methoxyphenyl)piperazin-1-yl)(4-(3-(4methylpiperazin-1-yl)propoxy)phenyl)methanone derivatives (scaffold-III) 4.3 4-(3-(4-ethylpiperazin-1-yl)propoxy)-N-phenylbenzamide (scaffold-IV) and (4-(3-(4-ethylpiperazin-1-yl)propoxy)phenyl)(4-(2-methoxyphenyl)piperazin-1-yl)methanone derivatives (scaffold-V) 4.4 4-[3-(morpholin-4-yl)propoxy]-N-phenylbenzamide derivative (scaffold-VI) and (4-(2-methoxyphenyl)piperazin-1-yl)(4-(3morpholinopropoxy)phenyl)methanone derivatives (scaffold-VII) CYTOTOXICITY STUDIES 5.1 Cell growth inhibition/MTT assay 5.2 Principle 5.3 Protocol 5.4 Results and discussion DOCKING OF SYNTHESIZED COMPOUNDS 6.1 Docking for EGFRTK interactions 6.2 Methodology 6.3 Selection and validation of 3D crystal structure of EGFR 6.4 Docking results and discussion IN VITRO EVALUATION 7.1 In vitro screening of EGFRTK Inhibitors 7.2 ADP-Glo assay for Kinase activity 7.3 Results and discussion SUMMARY AND CONCLUSION FUTURE PERSPECTIVES REFERENCES 1.1. Cancer Cancer is one of the most dangerous diseases in today's modern world. Cancer is formed when normal cells lose their normal regulatory mechanisms that control growth and multiplication[1]. Abnormal growth of tissue is called neoplasm and when neoplasm also forms a mass, it is called as tumor. Neoplasm may not always be associated with tumor formation. These tumors can be of two types benign and malignant [2]. Benign tumors are non cancerous and are not life threatening. These kind of tumors grow slowly, composed of normal cells and do not spread to other tissues. Whereas malignant tumors grow fast (uncontrolled growth) and break off from mother tissue and spread to other tissues through blood and lymphatic system. The process of spreading is known as metastasis and at new site the growth continues to result in a condition known as metastatic cancer [3]. Based on tissue types, cancer may be classified as sarcoma, lymphoma, leukemia, adenoma and carcinoma as discussed below [4]. Sarcoma: It includes cancer of bone, cartilage, fat, muscles and other connective tissues. Lymphoma: It includes cancer of lymph nodes and immune system tissues. Leukemia: It includes cancer of bone marrow and often accumulates in blood stream. Adenoma: It includes cancer of the glandular type of tissue like thyroid cancer. Carcinoma: It includes cancer of lung, breast, pancreas and colon. 1.1.1 Carcinoma Carcinoma is most common type of cancer. Carcinoma arises from epithelial cells and may invade adjacent tissue, organs and metastasizes all organs. Breast, prostate, pancreatic, lung and colon cancers are some examples of carcinoma. Colorectal cancer: Colorectal cancer starts in the colon or rectum hence named as colon cancer or rectal cancer, depending on where it starts. Colon and rectal cancers are often grouped together as they have common signs and symptoms. Most colorectal cancers begin as uncontrolled growth on the inner lining of the colon or rectum called a polyp. Some of the polyps may develop as cancer over the course of time, but not all. The transformation into a cancer depends on the kind of polyp and conditions, for example, hyperplastic polyps and inflammatory polyps are not pre-cancerous. Improvement in survival is because of early diagnosis of certain cancers and improvements in treatment strategies [6] [7]. Indian context With more than 1,300 deaths reported every day, cancer in India has become one of the major causes of death. National Cancer Registry Program (NCRP) of the Indian Council of Medical Research (ICMR) estimates that, cancer mortality rate in the country increased by about six
2022
One of the leading causes of death worldwide these days is cancer, and new anticancer drugs have been developed to treat it with all the vigor of the advancement of science and technology. Unfortunately, these drugs are very expensive, and besides, they cause great economic hardship for cancer patients and society as a whole. On the other hand, the deployment of hazardous chemicals, and especially the common commercial solvents in the production of anticancer drugs, causes environmental pollution thus contributing to the drug purification costs. Herein, recent FDA-approved anticancer drugs in 2020-2021, their mechanism of action, financial challenges, and associated environmental hazards are deliberated, with possible solutions that may reduce not only the costs of the drugs but also the environmental pollution involved in the synthesis of anticancer drugs via greener pathways by appropriate substitution.