ST. Xavier's College Ahmedabad.
Curcumin, a polyphenolic compound derived from Curcuma longa, has demonstrated remarkable anticancer properties across various malignancies. However, its clinical application has been severely limited by poor bioavailability, chemical instability, and rapid metabolic degradation primarily attributed to the ?-diketone moiety. To address these limitations, researchers have developed mono-carbonyl analogs of curcumin (MACs) that eliminate the unstable ?-diketone structure while retaining or enhancing therapeutic efficacy. This comprehensive review examines the synthesis, structure-activity relationships, mechanisms of action, and therapeutic potential of mono-carbonyl curcumin analogs in cancer therapy. We analyze prominent analogs including EF24, GO-Y030, GO-Y022, GO-Y078, EF31, UBS109, and other emerging compounds, their superior anticancer activity (10-50 fold higher potency), improved pharmacokinetic profiles (up to 60% bioavailability), and reduced toxicity compared to parent curcumin. These analogs demonstrate enhanced stability, increased water solubility, and potent anticancer effects through multiple mechanisms including apoptosis induction, cell cycle arrest, inhibition of oncogenic pathways (NF-?B, STAT3, PI3K/Akt), epithelial-mesenchymal transition suppression, and microRNA regulation. Current evidence suggests that mono-carbonyl curcumin analogs represent a promising class of anticancer agents with significant potential for clinical translation in various cancer types including breast, prostate, colon, lung, pancreatic, and cholangiocarcinoma.
Cancer remains one of the leading causes of morbidity and mortality worldwide, with an estimated 19.3 million new cases and 10 million cancer-related deaths in 2020 [1]. The continuous search for novel therapeutic strategies has led researchers to explore natural products as potential sources of anticancer agents. Among these, curcumin (diferuloylmethane), the primary bioactive component of turmeric (Curcuma longa), has emerged as one of the most extensively studied natural compounds due to its remarkable pleiotropic properties and promising anticancer activities [2,3]. Curcumin exhibits a diverse spectrum of biological activities including anti-inflammatory, antioxidant, antimicrobial, and anticancer properties [4]. Extensive preclinical studies have demonstrated its efficacy against various cancer types, including breast, prostate, colon, lung, pancreatic, and hematological malignancies [5,6]. The compound's anticancer effects are mediated through multiple mechanisms, including induction of apoptosis, cell cycle arrest, inhibition of angiogenesis, suppression of metastasis, and modulation of various signaling pathways such as NF-κB, PI3K/Akt, MAPK, and Wnt/β-catenin [7,8]. Despite its promising therapeutic potential, curcumin's clinical application has been severely hampered by several pharmacological limitations. The compound exhibits poor oral bioavailability (less than 1%), rapid metabolism, limited tissue distribution, and chemical instability under physiological conditions [9,10]. The β-diketone moiety in curcumin's structure contributes significantly to these limitations, making the compound susceptible to degradation through various metabolic pathways including glucuronidation, sulfation, and reduction by aldo-keto reductases [11,12].
To overcome these challenges, researchers have developed numerous curcumin analogs with improved pharmacological properties. Among these, mono-carbonyl analogs of curcumin (MACs) have emerged as particularly promising candidates. These compounds eliminate the problematic β-diketone moiety while maintaining or enhancing the therapeutic efficacy of the parent compound [13,14]. This structural modification results in improved stability, enhanced bioavailability, and often superior anticancer activity compared to curcumin. Recent advances in the synthesis and biological evaluation of mono-carbonyl curcumin analogs have revealed their tremendous potential as next-generation anticancer agents. Notable compounds such as EF24, GO-Y030, GO-Y022, and others have demonstrated IC50 values 10-50 times lower than curcumin across various cancer cell lines, with enhanced bioavailability and improved safety profiles [15,16]. This comprehensive review examines the current state of mono-carbonyl curcumin analogs as anticancer agents, focusing on their synthesis, structure-activity relationships, mechanisms of action, and therapeutic potential for clinical translation.
2. Chemical Structure and Synthetic Approaches
2.1 Mono-carbonyl analogs of curcumin are characterized by the replacement of curcumin's β-diketone linker with a single carbonyl group, typically in the form of α,β-unsaturated ketones. This structural modification eliminates the major source of instability while preserving the essential pharmacophoric elements responsible for biological activity [17]. The general structure consists of two aromatic rings connected by a carbon chain containing a single carbonyl group, with various substituents on the aromatic rings to modulate activity and selectivity [18]. The β-diketone moiety in curcumin exists in equilibrium between its keto and enol tautomers, with the latter being predominant in solution. This tautomerization contributes to the compound's instability and susceptibility to metabolic degradation [19]. By eliminating one of the carbonyl groups, MACs maintain conjugated system necessary for biological activity while significantly improving chemical stability.
2.2 Synthetic Methodologies
The synthesis of mono-carbonyl curcumin analogs primarily employs Claisen-Schmidt aldol condensation reactions. Several synthetic approaches have been developed and optimized over the years:
2.2.1 Base-Catalyzed Condensation
The most common method involves the reaction of appropriate aromatic aldehydes with ketones (acetone, cyclohexanone, or cyclopentanone) under basic conditions using sodium hydroxide or sodium methoxide as catalysts [20]. This approach typically yields products with good purity and moderate to high yields (57-89%). The reaction mechanism proceeds through the formation of an enolate ion from the ketone, followed by nucleophilic attack on the aldehyde carbonyl and subsequent dehydration [21].
2.2.2 Acid-Catalyzed Reactions Alternative approaches employ acid catalysts such as hydrochloric acid or p-toluenesulfonic acid, particularly useful for reactions involving phenolic aldehydes that may not react well under basic conditions due to phenolate formation [22]. These methods are especially effective for synthesizing analogs with free hydroxyl groups, such as GO-Y078 derivatives.
2.2.3 Microwave-Assisted Synthesis
Recent developments include microwave-assisted synthesis, which offers advantages such as reduced reaction times (from days to hours), cleaner products, higher yields, and improved environmental sustainability [23]. This method has been successfully applied to synthesize various MACs with enhanced efficiency and reduced side product formation.
2.2.4 Heterocyclic Scaffold-Based Synthesis
More sophisticated analogs incorporate heterocyclic scaffolds such as piperidine (EF24 series), tropane, or granatanone frameworks to further enhance water solubility and biological activity [24,25]. These synthetic approaches often require multi-step procedures but result in compounds with superior pharmacological properties.
3. Prominent Mono-Carbonyl Curcumin Analogs
3.1 EF24 (3,5-bis(2-fluorobenzylidene) piperidin-4-one)
EF24 represents one of the most extensively studied and clinically promising mono-carbonyl curcumin analogs. First synthesized by Adams et al. in 2004, EF24 demonstrates significantly enhanced anticancer activity compared to curcumin, with IC50 values 10-20 times lower than the parent compound across various cancer cell lines [26,27].
3.1.1 Structural Features
EF24 features a piperidine ring as the central linker with two fluorinated benzylidene substituents. The fluorine atoms enhance the compound's metabolic stability and improve its pharmacokinetic profile. The piperidine nitrogen can be protonated under physiological conditions, contributing to improved water solubility compared to curcumin [28].
3.1.2 Anticancer Mechanisms
NF-κB Pathway Inhibition: EF24 selectively inhibits IκB kinase (IKK), preventing NF-κB nuclear translocation and transcriptional activity. This mechanism is particularly important as NF-κB regulates numerous genes involved in cell survival, proliferation, and metastasis [29,30].
Cell Cycle Arrest: EF24 induces G2/M phase arrest through modulation of cyclin B1, CDC2, and survivin expression. This arrest is often accompanied by DNA damage checkpoint activation [31].
Apoptosis Induction: The compound activates caspase-3 and promotes PARP cleavage leading to programmed cell death. EF24 primarily activates the intrinsic apoptotic pathway through mitochondrial membrane potential disruption [32].
MicroRNA Regulation: EF24 downregulates oncogenic miR-21 while enhancing tumor suppressor miRNAs, affecting multiple downstream targets including PTEN and PDCD4 [33].
HIF-1α Inhibition: EF24 suppresses hypoxia-inducible factor-1α activity, affecting angiogenesis and metabolic adaptation in cancer cells [34].
3.1.3 Clinical Potential
EF24 has demonstrated efficacy in various cancer models including breast, prostate, ovarian, colon, and cholangiocarcinoma. The compound shows enhanced bioavailability (60% in mice) compared to curcumin and exhibits low toxicity to normal cells [35,36]. Several drug delivery systems including liposomal formulations and targeted conjugates have been developed to further enhance its therapeutic potential.
3.2 GO-Y030 (1,5-bis(3,5-dimethoxyphenyl)-1,4-pentadiene-3-one)
GO-Y030 represents another highly promising mono-carbonyl analog with superior anticancer activity. This compound features methoxy substituents that enhance its biological activity and selectivity [37].
3.2.1 Enhanced Potency
GO-Y030 demonstrates >10-fold higher anticancer activity than curcumin, with GI50 values as low as 0.3 μM against HCT116 colorectal cancer cells. The compound shows remarkable selectivity for cancer cells over normal cells [38].
3.2.2 Multi-target Activity
GO-Y030 inhibits multiple oncogenic pathways including NF-κB, PI3K/Akt, JAK/STAT3, and IRF4. This multi-target approach contributes to its superior efficacy and reduced likelihood of resistance development [39].
3.2.3 Immunomodulatory Effects
Recent studies have revealed that GO-Y030 reduces regulatory T cell populations in tumor microenvironments, potentially enhancing anti-tumor immune responses. This immunomodulatory activity adds another dimension to its therapeutic potential [40].
3.2.4 Metabolic Effects
GO-Y030 inhibits glycolysis in melanoma cells, affecting tumor metabolism and energy production. This metabolic disruption contributes to its anti-metastatic effects [41].
3.3 GO-Y022 (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one)
Also known as FLLL11 or Deketomin®, GO-Y022 is a diarylpentanoid analog that forms naturally during curry cooking processes. This compound has shown promise in preventing oncogenesis in animal models [42].
3.3.1 STAT3 Inhibition
GO-Y022 prevents STAT3 activation in tumor cells, which is particularly relevant for cancers with constitutively active STAT3 signaling. This inhibition affects multiple downstream targets including survivin, cyclin D1, and Bcl-2 [43].
3.3.2 Cancer Prevention
GO-Y022 demonstrates significant chemopreventive effects in familial adenomatous polyposis (FAP) mice, suggesting potential applications in cancer prevention strategies [44].
3.4 GO-Y078 and Other Notable Analogs
GO-Y078, featuring asymmetric substitution patterns, demonstrates improved solubility (approximately 4-fold higher than GO-Y030) and enhanced anticancer activity. The compound shows superior activity in gastric cancer models and enhanced bioavailability [45].
Other notable analogs include:
4. Structure-Activity Relationships
Extensive structure-activity relationship (SAR) studies have revealed critical structural elements required for optimal anticancer activity in mono-carbonyl curcumin analogs [46,47]:
4.1 Electronic Effects
4.2 Linker Effects
4.3 Substitution Patterns
5. Mechanisms of Anticancer Action
Mono-carbonyl curcumin analogs exert their anticancer effects through multiple, interconnected mechanisms [48,49]:
5.1 Apoptosis Induction
MACs induce apoptosis primarily through the intrinsic (mitochondrial) pathway:
5.2 Cell Cycle Arrest
Most MACs induce cell cycle arrest, predominantly at the G2/M phase:
5.3 Oncogenic Pathway Inhibition
5.3.1 NF-κB Pathway
5.3.2 STAT3 Pathway
5.3.3 PI3K/Akt Pathway
5.4 Anti-Metastatic Effects
MACs demonstrate significant anti-metastatic properties:
5.5 Metabolic Modulation
Recent studies have revealed that MACs can modulate cancer cell metabolism:
6. Bioavailability and Pharmacokinetic Advantages
One of the primary advantages of mono-carbonyl curcumin analogs over parent curcumin is their dramatically improved pharmacokinetic profile [50,51]:
6.1 Enhanced Stability
6.2 Improved Bioavailability
6.3 Solubility Enhancement
7. Preclinical Efficacy and Safety Profile
Extensive preclinical studies have demonstrated the superior anticancer efficacy and safety of mono-carbonyl curcumin analogs across various cancer models [52,53]:
7.1 In Vitro Studies
Cell Line Studies:
Mechanistic Studies:
7.2 In Vivo Models
Xenograft Studies:
Metastasis Models:
Pharmacokinetic Studies:
7.3 Safety and Toxicological Profile
Acute Toxicity:
Chronic Toxicity:
8. Clinical Translation Potential and Current Status
The promising preclinical data for mono-carbonyl curcumin analogs has generated increasing interest in clinical translation [54,55]:
8.1 Current Clinical Status
While curcumin itself has been evaluated in numerous clinical trials for various cancer types, specific clinical trials for mono-carbonyl analogs are still limited. However, several compounds are in various stages of preclinical development and early clinical evaluation:
8.2 Regulatory Considerations
8.3 Clinical Development Strategies
9. Challenges and Future Perspectives
Despite the promising potential of mono-carbonyl curcumin analogs, several challenges remain [56,57]:
9.1 Scientific Challenges
9.2 Technical Challenges
9.3 Clinical and Regulatory Challenges
10. Emerging Developments and Future Directions
10.1 Next-Generation Analogs
10.2 Advanced Drug Delivery Systems
10.3 Combination Strategies
10.4 Precision Medicine Approaches
11. CONCLUSION
Mono-carbonyl analogs of curcumin represent a significant advancement in the development of curcumin-based anticancer therapeutics. These compounds have successfully addressed the major limitations of parent curcumin—poor bioavailability, chemical instability, and rapid metabolism—while maintaining or enhancing therapeutic efficacy. The elimination of the β-diketone moiety has resulted in compounds with improved chemical stability, enhanced bioavailability (up to 60-fold improvement), and superior pharmacokinetic properties. The extensive preclinical data demonstrates that MACs exhibit potent anticancer activity (10-50 fold higher than curcumin) through multiple mechanisms including apoptosis induction, cell cycle arrest, oncogenic pathway inhibition, and anti-metastatic effects. Prominent analogs such as EF24, GO-Y030, GO-Y022, and GO-Y078 have shown particular promise across various cancer types, with some demonstrating remarkable selectivity for cancer cells over normal cells. The favorable safety profile, enhanced bioavailability, and multi-target mechanism of action position these compounds as promising candidates for clinical development. However, successful clinical translation will require addressing challenges related to large-scale synthesis, formulation optimization, biomarker development, and regulatory approval.
Future research should focus on: (1) completing comprehensive toxicological studies to support clinical development; (2) developing standardized synthetic and analytical methods for quality control; (3) identifying predictive biomarkers for patient selection; (4) exploring rational combination strategies with existing therapies; and (5) investigating novel formulation and delivery approaches. The field of mono-carbonyl curcumin analogs represents a compelling example of how medicinal chemistry approaches can transform a promising but problematic natural product into viable therapeutic agents. As our understanding of their mechanisms of action continues to evolve and clinical studies progress, these compounds have the potential to fulfill their promise as next-generation curcumin-based anticancer therapeutics, offering new hope for cancer patients while minimizing the toxicities associated with conventional chemotherapy. With continued research and development efforts, mono-carbonyl curcumin analogs may well become valuable additions to the anticancer therapeutic armamentarium, representing a new paradigm in natural product-derived drug development that combines the best aspects of traditional medicine with modern pharmaceutical science.
REFERENCES
Amankumar Kansagara*, Vishakha Daga, Mono-Carbonyl Analogs of Curcumin: Enhanced Therapeutic Agents for Cancer Treatment with Superior Bioavailability and Anticancer Efficacy, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 9, 213-230 https://doi.org/10.5281/zenodo.17037749
10.5281/zenodo.17037749
