Structural Modifications of Curcumin toward Clinical Applications

Curcumin and analogues against head and neck cancer: From drug delivery to molecular mechanisms

Curcumin analogues and their hybrid molecules as multifunctional drugs

Naturally occurring phytochemicals or plant derivatives are now being explored extensively for their health's benefits and medicinal uses. The therapeutic effect of phytochemicals has been reported in several pathophysiological settings such as inflammatory disorders, metabolic disorders, liver dysfunction, neurodegenerative disorders, and nephropathies. However, the most warranted therapeutic effects of phytochemicals were mapped to their anticancerous and chemopreventive action. Moreover, combining phytochemicals with standard chemotherapy has shown promising results in cancer therapy with minimal side effects and better efficacy. Many phytochemicals, like curcumin, resveratrol, and epigallocatechin-3-gallate, have been extensively investigated for their chemopreventive as well as chemotherapeutic effects. However, poor bioavailability, low solubility, hydrophobicity, and obscure target specificity restrict their therapeutic applications in the clinic. There has been a continually increasing interest to formulate nanoformulations of phytochemicals by using various nanocarriers, such as liposomes, micelles, nanoemulsions, and nanoparticles, to improve their bioavailability and target specificity, thereby maximizing the therapeutic potential. In the present review, we have summarized chemopreventive as well as chemotherapeutic action of some common phytochemicals and their major limitations in clinical application. Also, we have given an overview of strategies that can improve the efficacy of phytochemicals for their chemotherapeutic value in clinical settings.

Natural compounds have emerged as promising therapeutic agents for treating cancers such as multiple myeloma (MM). However, poor bioavailability, low stability, and suboptimal targeting often limit their clinical efficacy. Recent advances in nanotechnology have addressed these limitations by utilizing nanoparticle (NP) carriers to enhance the therapeutic potential of natural compounds through improved solubility, stability, and selective delivery to cancer cells. This review explores the inhibitory effects of key natural compounds on MM cells, including 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivatives, caffeic acid phenethyl ester (CAPE) and its derivatives, xanthohumol (XN) and its derivatives, resveratrol (RSV) and its derivatives, curcumin (CUR), 3,4,5-trihydroxybenzoic acid (gallic acid; GA), and evodiamine (EVO). These compounds exhibit potent anti-proliferative, pro-apoptotic, and anti-inflammatory properties through the modulation of signaling pathways such as NF-κB, STAT3, and PI3K/Akt, which are critical in MM pathogenesis. Despite their therapeutic promise, the clinical application of these natural agents has been hampered by pharmacokinetic challenges. NP carriers, including liposomes, polymeric NPs, and lipid-based nanocarriers, have been engineered to improve these compounds’ bioavailability and targeted delivery, enhancing their cytotoxicity against MM cells. For instance, CDDO and its derivatives encapsulated in NPs have demonstrated increased intracellular accumulation and improved inhibition of NF-κB activity. Similarly, NP formulations of CAPE, XN, and RSV have enhanced anti-MM effects through improved stability and sustained drug release. CUR, known for its poor water solubility, has seen its therapeutic potential augmented through NP delivery systems, enabling higher drug concentrations at tumor sites. Though structurally distinct, GA and EVO have benefited from NP-based enhancement, exhibiting improved bioavailability and selective targeting of MM cells. This review highlights the promising role of NP carriers in overcoming the pharmacokinetic limitations of natural compounds, offering new avenues for more effective MM therapies.

Therapeutic potential of curcumin and curcumin analogues in rheumatology

Butrin, a flavonoid glycoside derived from Butea monosperma, has garnered attention for its neuroprotective effects attributed to its multifaceted pharmacological profile. It modulates dopamine and norepinephrine levels and exhibits antioxidant, antiinflammatory, and mitochondrial-protective actions. These properties position butrin as a promising candidate for therapeutic intervention in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. This review consolidates mechanistic insights, preclinical evidence, and therapeutic perspectives of butrin to assess its potential clinical applicability in managing neurodegenerative disorders. This review critically analyzes existing preclinical studies on the neuroprotective effects of butrin. Emphasis is placed on its mechanisms of action, including mitigation of oxidative stress, suppression of neuroinflammation, enhancement of neurotrophic factors, and preservation of mitochondrial integrity. Additionally, the review explores current limitations in clinical translation and evaluates emerging drug delivery strategies aimed at improving its therapeutic potential. Preclinical evidence indicates that butrin effectively counters excitotoxicity and protein aggregation, key pathological features of neurodegenerative disorders. It attenuates neuropathological processes and demonstrates synergistic effects when combined with other neuroprotective and anti-inflammatory agents. Nonetheless, its poor bioavailability and limited ability to cross the blood-brain barrier remain significant barriers to clinical application. Despite its promising pharmacological profile, the clinical translation of butrin is constrained by absorption challenges and suboptimal pharmacokinetics. Innovative strategies, such as nanocarrier-based delivery systems, drug repurposing, and combination therapies, may enhance its therapeutic efficacy. Addressing these limitations is crucial for advancing butrin from bench to bedside. Butrin exhibits compelling neuroprotective properties supported by robust preclinical data. However, large-scale clinical trials are essential to validate its efficacy. Integrating advanced drug delivery systems and personalized medicine approaches may unlock its full potential in managing neurodegenerative diseases.

Didemnins, a class of cyclic depsipeptides derived from marine organisms exhibit notable anticancer properties. Among them, Didemnin B has been extensively researched for its strong antitumor activity and progression to clinical trials. Nonetheless, its clinical application has been impeded by challenges like poor bioavailability and dose-limiting toxicity. This review aims to provide a comprehensive analysis of the anticancer mechanisms of Didemnins, particularly Didemnin B, by examining studies that investigate their anticancer properties, mechanisms of action, pharmacokinetics, and clinical outcomes, while exploring their potential as therapeutic agents in cancer treatment. A comprehensive review of the literature was conducted using scientific databases, including PubMed, Google Scholar and ScienceDirect. Didemnin B has been shown to exert its anticancer effects primarily through the inhibition of protein synthesis, induction of apoptosis, and disruption of cell-cycle progression. Despite promising preclinical results, clinical trials have revealed substantial toxicity, particularly neuromuscular and hepatic, which significantly constrains its therapeutic potential. Recent progress in developing semisynthetic derivatives, including Dehydrodidemnin B (Plitidepsin, Aplidin), have led to improved efficacy and reduced toxicity. Didemnins, especially Didemnin B, hold promise as anticancer agents. However, future research should focus on optimizing delivery methods, reducing toxicity, and exploring combination therapies to enhance their therapeutic potential in oncology.

Vasoactive intestinal peptide (VIP) is an anti-inflammatory neuropeptide recently identified as a potential antimicrobial peptide. To overcome the metabolic limitations of VIP, we modified the native peptide sequence and generated two stable synthetic analogues (VIP51 and VIP51(6-30)) with better antimicrobial profiles. Herein we investigate the effects of both VIP analogues on cell viability, membrane integrity, and ultrastructure of various bacterial strains and Leishmania species. We found that the two VIP derivatives kill various non-pathogenic and pathogenic Gram-positive and Gram-negative bacteria as well as the parasite Leishmania major through a mechanism that depends on the interaction with certain components of the microbial surface, the formation of pores, and the disruption of the surface membrane. The cytotoxicity of the VIP derivatives is specific for pathogens, because they do not affect the viability of mammalian cells. Docking simulations indicate that the chemical changes made in the analogues are critical to increase their antimicrobial activities. Consequently, we found that the native VIP is less potent as an antibacterial and fails as a leishmanicidal. Noteworthy from a therapeutic point of view is that treatment with both derivatives increases the survival and reduces bacterial load and inflammation in mice with polymicrobial sepsis. Moreover, treatment with VIP51(6-30) is very effective at reducing lesion size and parasite burden in a model of cutaneous leishmaniasis. These results indicate that the VIP analogues emerge as attractive alternatives for treating drug-resistant infectious diseases and provide key insights into a rational design of novel agents against these pathogens.

Curcumin is a natural polyphenol phytochemical derived from turmeric with antioxidant, anti-inflammatory, and anticancer properties but is concerned about poor solubility in water, absorption, and metabolic stability. Potent metastatic osteosarcoma is the most common primary bone cancer in children, adolescents, and young adults. It is responsible for low survival rates because of its high rate of metastasis to the lungs. To improve poor bioavailability, numerous curcumin analogs were developed to possess anticancer characteristics through a variety of biological pathways involved in cytotoxicity, proliferation, autophagy, sensitizing chemotherapy, and metastases. This review provides an overview of their various pharmacological functions, molecular mechanisms, and therapeutic potential as a remedy for human osteosarcoma. To enhance therapeutic efficacy, several liposomal nanoparticles, nanocarriers, multifunctional micelles, and three-dimensional printed scaffolds have also been developed for the controlled delivery of curcumin targeting human osteosarcoma cells. Consequently, curcumin and several potential analogs and delivery formulations are optimistic candidates to improve the currently available strategy for human osteosarcoma. However, further insight into the mechanism of action of promising curcumin analogs and the development of carriers in clinical trials of osteosarcoma needs to be investigated to improve their overall potency and clinical utility, in particular the anti-metastatic effect.

Rheumatoid arthritis (RA) is a long-term inflammatory disease that causes synovial joint inflammation, which causes pain, stiffness, and gradual joint destruction. In addition to having a major effect on quality of life, the illness may result in systemic problems. The goal of current treatment approaches, which include biologics, corticosteroids, disease-modifying antirheumatic medications (DMARDs), and nonsteroidal anti-inflammatory medicines (NSAIDs), is to manage symptoms and halt the course of the disease. These treatments, however, frequently have problems like poor effectiveness, systemic side effects, and exorbitant expenses. Advanced, tailored medication delivery methods like nanocarriers are necessary because managing RA is made more difficult by poor patient adherence and limited targeting of inflammatory areas. Berberine and curcumin are bioactive natural compounds with significant therapeutic potential, particularly in managing inflammatory and autoimmune conditions like rheumatoid arthritis (RA). Berberine exhibits potent anti-inflammatory, immunomodulatory, and antioxidant properties, effectively suppressing pro-inflammatory cytokines and oxidative stress Curcumin, a polyphenol derived from turmeric, also demonstrates strong anti-inflammatory and antioxidant effects, inhibiting key molecular pathways involved in RA pathogenesis, such as NF-κB activation. Despite their promising pharmacological profiles, both compounds face challenges like poor water solubility, low bioavailability, and rapid metabolism. Advanced drug delivery systems, such as nanostructured lipid carriers, offer a solution to enhance their therapeutic efficacy and clinical applicability. Nanostructured lipid carriers (NLCs) are advanced drug delivery systems offering numerous advantages for therapeutic applications. Their unique structure, combining solid and liquid lipids, enhances drug solubility, stability, and bioavailability. NLCs enable controlled and sustained drug release, reducing dosing frequency and improving patient compliance. They can protect sensitive drugs like berberine and curcumin from degradation, extending their shelf life. Additionally, NLCs can be functionalized for targeted delivery, increasing drug accumulation at inflamed joints in conditions like rheumatoid arthritis while minimizing systemic side effects. Their biocompatibility and scalability make NLCs a promising platform for improving the clinical efficacy of challenging therapeutic agents. Berberine and curcumin exhibit remarkable anti-inflammatory and antioxidant properties, making them promising candidates for managing rheumatoid arthritis (RA). However, their clinical potential is limited by poor solubility and bioavailability. Nanostructured lipid carriers (NLCs) address these limitations by enhancing drug stability, targeted delivery, and controlled release. Preclinical studies demonstrate improved therapeutic efficacy of NLC formulations in RA models, though clinical translation remains limited. Future research should focus on optimizing NLC designs for enhanced targeting, scalability, and regulatory compliance. Combining these carriers with advanced therapeutic strategies offers a pathway to more effective and patient-friendly RA treatments, bridging lab discoveries to clinical practice

Camptothecin (CPT), an alkaloid isolated from the Camptotheca tree, has demonstrated significant anticancer properties in a range of malignancies. However, its therapeutic efficacy is limited by its hydrophobicity, poor bioavailability, and systemic toxicity. Derivatives, analogues, and nanoformulations of CPT have been synthesized to overcome these limitations. The aim of this review is to comprehensively analyze existing studies to evaluate the therapeutic efficacy, mechanistic aspects, and clinical potential of CPT and its modified forms, including derivatives, analogues, and nanoformulations, in cancer treatment. A comprehensive literature review was performed using PubMed/Medline, Scopus, and Web of Science databases; articles were selected based on specific inclusion criteria, and data were extracted on the pharmacological profile, clinical studies, and therapeutic efficacy of CPT and its different forms. Current evidence suggests that derivatives and analogues of CPT have improved water solubility, bioavailability, and reduced systemic toxicity compared to CPT. Nanoformulations further enhance targeted delivery and reduce off-target effects. Clinical trials indicate promising outcomes with enhanced survival rates and lower side effects. CPT and its modified forms hold significant promise as potent anticancer agents. Ongoing research and clinical trials are essential for establishing their long-term efficacy and safety; the evidence overwhelmingly supports further development and clinical testing of these compounds.

Curcumin is a natural product with multiple biological activities and numerous potential therapeutic applications. However, its poor systemic bioavailability fails to explain the potent pharmacological effects and hinders its clinical application. Using experimental and theoretical approaches, we compared curcumin and its degradation products for its biological activities against Alzheimer’s disease (AD), including the superoxide anion radical (O2.–)-scavenging activity, Aβ fibrils (fAβ) formation-inhibiting activity, and enzymatic inhibition activity. We showed that compared to the parent compound curcumin, the degradation products mixture possessed higher O2.–-scavenging activity and stronger inhibition against fAβ formation. The docking simulations revealed that the bioactive degradation products should make important contribution to the experimentally observed enzymatic inhibition activities of curcumin. Given that curcumin is readily degraded under physiological condition, our findings strongly suggested that the degradation products should make important contribution to the diverse biological activities of curcumin. Our novel findings not only provide novel insights into the complex pharmacology of curcumin due to its poor bioavailability, but also open new avenues for developing therapeutic applications of this natural product.

Niclosamide, an FDA-approved anti-parasitic drug, has demonstrated significant potential as a repurposed anti-cancer agent due to its ability to interfere with multiple oncogenic pathways. However, its clinical application has been hindered by poor solubility and bioavailability. Lipid-based nanocarrier systems such as liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and lipid nanoemulsions (LNE), along with lipid prodrugs, have successfully been employed by researchers to overcome these limitations and improve niclosamide’s pharmacokinetic profile. Lipids are the core organic compounds which serve as the foundation of these advanced drug delivery methods and in turn play a critical role in enhancing niclosamide’s therapeutic efficacy through improving drug solubility and bioavailability. Lipid-based nanoparticles encapsulate niclosamide, protect it from degradation, facilitate drug delivery and release, and may facilitate targeted delivery in the future. While niclosamide holds significant potential as an anticancer agent due to its multi-pathway inhibitory effects, the challenges associated with its poor bioavailability and rapid clearance underscore the need for innovative delivery methods and chemical modifications to unlock its full therapeutic potential. This review aims to present the latest instances of lipid-based delivery of niclosamide and to compile successful strategies which may be employed when aiming to develop effective anticancer therapies.

There is a crucial need to develop new effective drugs for Alzheimer's disease (AD) as the currently available AD treatments provide only momentary and incomplete symptomatic relief. Amongst natural products, curcumin, a major constituent of turmeric, has been intensively investigated for its neuroprotective effect against β-amyloid (Aβ)-induced toxicity in cultured neuronal cells. The ability of curcumin to attach to Aβ peptide and prevent its accumulation is attributed to its three structural characteristics such as the presence of two aromatic end groups and their co-planarity, the length and rigidity of the linker region and the substitution conformation of these aromatics. However, curcumin failed to reach adequate brain levels after oral absorption in AD clinical trials due to its low water solubility and poor oral bioavailability. A number of new curcumin analogs that mimic the active site of the compound along with analogs that mimic the curcumin anti-amyloid effect combined with anticholinesterase effect have been developed to enhance the bioavailability, pharmacokinetics, water solubility, stability at physiological conditions and delivery of curcumin. In this article, we have summarized all reported synthetic analogs of curcumin showing effects on β-amyloid and discussed their potential as therapeutic and diagnostic agents for AD.

Phytochemicals, particularly polyphenols, play a crucial role in modern healthcare due to their preventive and therapeutic properties. Among these, epigallocatechin-3-gallate (EGCG), a potent catechin found in green tea, exhibits exceptional antioxidant, anti-inflammatory, and disease-modulating effects, making it a promising candidate for managing cancer, diabetes, and cardiovascular disorders. However, its clinical translation is hindered by instability and poor bioavailability. Recent advancements in nanotechnology have addressed these limitations through innovative nano-formulations that enhance encapsulation, stability, and targeted delivery, thereby improving therapeutic efficacy. This review comprehensively examines the latest research on EGCG’s health benefits, its pharmacokinetic challenges, and the development of nanomaterial-based delivery systems to maximise its biomedical potential. By critically evaluating current strategies and future directions, this work highlights the transformative role of nano-engineered EGCG in bridging the gap between preclinical promise and clinical application.