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Chirality and natural products are two pivotal concepts within the domains of chemistry and biology. Chirality is a molecular property that renders it non-superimposable on its mirror image, while natural products are chemical compounds biosynthesized by living organisms. This article delves into the intricate relationship between chirality and natural products, elucidating their significance in diverse applications.
Chirality is a critical factor in the discovery of drugs derived from natural products. Natural products are intricate organic molecules biosynthesized by living organisms, exhibiting a broad spectrum of biological activities. Many of these molecules are chiral, and their biological activities are profoundly influenced by their stereochemistry. Consequently, comprehending the role of chirality in the discovery of natural products drug is indispensable for the advancement of novel therapeutics.
Chirality and biological activity
The interaction between a chiral molecule and a biological target is profoundly influenced by the molecule's stereochemistry. This is attributed to the fact that biological molecules, including enzymes, receptors, and transporters, are inherently chiral and possess specific three-dimensional structures. Hence, the interaction between a chiral molecule and a biological target can be significantly influenced by the molecule's orientation and spatial configuration.
A case in point is the drug thalidomide, which was administered in the 1950s and 1960s to alleviate morning sickness in pregnant women. It was later discovered to have severe teratogenic effects on the developing fetus. Subsequent investigations revealed that the drug was a chiral molecule, and the enantiomer responsible for the therapeutic effect was distinct from the enantiomer responsible for the teratogenic effect. This incident underscored the importance of chirality in drug development.
Natural products
Natural products are chemical compounds biosynthesized by living organisms, including plants, animals, and microorganisms. These compounds play a pivotal role in various biological processes, such as defense against predators and pathogens, inter-organism communication, and regulation of metabolic pathways. Natural products have been a source of inspiration for drug discovery and development for centuries. Many currently used drugs are derived from natural products, such as penicillin, derived from the fungus Penicillium, and aspirin, derived from willow bark. Natural products are also used as leads for drug development, where their structure is modified to enhance their efficacy, selectivity, and pharmacokinetic properties.
Chirality and natural products
Chirality plays a critical role in the biological activity of natural products. Enantiomers of natural products often exhibit different biological activity due to their distinct interactions with biological systems. For instance, limonene, a natural product found in citrus fruits, exists in an enantiomeric pair. The (R)-limonene has an orange smell, while its mirror-image version exhibits a lemon smell. Another example is the alkaloid morphine, found in the opium plant (Papaver Sommniferum), which contains five chiral centers and hence the molecule can exist in 32 stereoisomers. Only the levo-isomer of morphine with stereodescriptors (5R, 6S, 9R, 13S,14R) has the desired narcotic analgesic activity.
Similarly, quinine carries four chiral centers and exists in 16 stereo-isomeric forms, and the levo-quinine with the configuration (3R, 4S, 8S, 9R) has the desired anti-malarial activity. Unichirality is the hallmark of many molecules from nature.
The study of chirality in natural products is essential for understanding their biological activity and developing new drugs. Chiral natural products can be isolated from their natural sources, and their enantiomers can be separated using various chromatographic techniques. The isolated enantiomers can then be tested for their biological activity, which can lead to the discovery of new drugs or natural product-based scaffolds for drug development.
The synthesis of chiral natural products is also an essential aspect of drug discovery and development. The synthesis of chiral compounds is challenging, and the development of efficient synthetic routes is crucial for the production of enantiomerically pure compounds.
Case studies
Several case studies illustrate the importance of chirality in natural products. For instance, Paclitaxel (Taxol), derived from the Pacific yew tree, is a highly effective anticancer agent. The compound is chiral, and its anticancer activity is attributed to a specific enantiomer. Synthetic efforts have focused on isolating and producing the active enantiomer, as the inactive form does not possess the same therapeutic benefits.
Another example is Camptothecin, a potent anticancer natural product discovered in the bark and stem of the Camptotheca acuminata tree. The compound is chiral, and its derivatives, such as irinotecan and topotecan, are used as chemotherapy drugs. The chirality of these molecules plays a crucial role in their interactions with cellular targets, contributing to their pharmacological effects. (S)-Campothecin is found to be biologically active.
Artemisinin: A natural product extracted from the sweet wormwood plant (Artemisia annua), is highly effective against malaria, one of the deadliest infectious diseases globally. Artemisinin contains several chiral centers, and its therapeutic activity is attributed to a specific enantiomer. Understanding and utilizing the correct enantiomer have been essential in producing effective antimalarial drugs.
Galantamine: Galantamine is a natural product derived from the snowdrop plant (Galanthus spp.) and other members of the Amaryllidaceae family. It is used to treat Alzheimer's disease. Galantamine is chiral, and the specific enantiomer responsible for the desired pharmacological effects is isolated and utilized in the drug formulation.
Ergotamine: Ergotamine is a natural product produced by the ergot fungus (Claviceps purpurea). Historically, it has been used to treat migraines and has been the basis for the development of other antimigraine drugs. Ergotamine contains multiple chiral centers, and the pharmacological activity resides in specific enantiomers.
Tools to determine stereochemistry of natural products
The importance of chirality in natural product drug discovery means that the stereochemistry of a natural product must be determined and understood before its biological activity can be fully elucidated. This can be a difficult task, particularly for complicated molecules with numerous chiral centers. The stereochemistry of these complicated molecules is determined using a variety of analytical methods and tools. Some of the most popular approaches are listed below.
Nuclear magnetic resonance (NMR) spectroscopy: Nuclear magnetic resonance (NMR) spectroscopy is a potent method for figuring out the relative and absolute stereochemistry of natural products. It helps scientists determine the relative positions of substituents and stereocenters by giving details about the spatial arrangement of protons and carbons in the molecule.
X-ray crystallography: The three-dimensional structure of crystalline substances can be ascertained using the X-ray crystallography technique. By revealing the precise positions of atoms in the crystal lattice, it can provide precise information about the absolute stereochemistry of natural products.
Mass spectrometry: Utilizing mass spectrometry, it is possible to ascertain the molecular weight and fragmentation pattern of natural products. By analyzing the fragmentation pathways, one can infer the relative stereochemistry of the molecule.
Circular dichroism (CD): CD spectroscopy measures the differential absorption of left and right-handed circularly polarized light. It can be used to determine the overall stereochemistry of chiral molecules and provides valuable information about the secondary structure of proteins and other biomolecules.
Optical rotation: The rotation of plane-polarized light as it passes through a chiral molecule is measured using the straightforward technique of optical rotation. It offers specific rotational information that can be used to ascertain a compound's exact configuration.
Chiroptical analysis: Chiroptical techniques, such as electronic circular dichroism (ECD) and vibrational circular dichroism (VCD), give information about the absolute configuration of chiral molecules and are especially helpful for complex natural products.
Computational methods: Molecular modeling and density functional theory (DFT) calculations are two examples of computational methods that can be used to predict natural product stereochemistry and compare experimental results with theoretical forecasts.
Chemical transformations and derivatization: Chemical transformations and derivatization of natural products can be employed to introduce known stereocenters or modify existing ones. Researchers can determine the stereochemistry by comparing the attributes of the original compound and its derivatives.
NMR-based methods: Nuclear overhauser effect spectroscopy (NOESY) and Rotating-frame overhauser effect spectroscopy (ROESY) are NMR-based methods that provide valuable information about spatial relationships between protons in a molecule, aiding in the determination of stereochemistry.
Conclusion
As a result, studying chirality in natural products is important for comprehending the active enantiomers of these complex molecules, which is important for which are crucial for harnessing their therapeutic potential and ensuring safe and effective drug treatments. Enantiomers of natural products often exhibit different biological activity, and the synthesis of enantiomerically pure compounds is crucial for drug development. As a result, chirality studies are now an important part of the process of discovering and developing new drugs, particularly when working with natural products.
(Valliappan Kannappan is founder, chiralpedia.com and Professor Emeritus, Karpagam College of Pharmacy, Coimbatore. Mohan Sellappan is Principal and Professor, Karpagam College of Pharmacy, Coimbatore. Kandasamy, CS is Professor, Karpagam College of Pharmacy, Coimbatore. Ilango Kaliappan is Professor and Dean, School of Pharmacy, Hindustan Inst. of Technology and Science, Chennai)
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