# Synthesis, Structure, and In Vitro Biological Evaluation of Semi-Synthetic Derivatives of Betulin
## 1 Introduction  
Since ancient times, plants have been a source of bioactive substances used in the treatment of many diseases [1, 2]. Among the organic compounds produced by plants, phytochemicals constitute a large group. Most of them are secondary plant metabolites characterized by diverse chemical structures. Secondary plant metabolites include, among others terpenoids, alkaloids, polyphenols, flavonoids, lignans, steroids, saponins, curcuminins, coumarins, and glucosides. Phytochemicals can be located in various parts of plants, usually in the bark, stem, root, leaves, flowers, fruit, or seeds. These compounds play an important role in the physiological processes of plants and protect them against threats such as drought, stress, environmental pollution, UV radiation, and pathogens [3, 4, 5]. The structural diversity of natural compounds of plant origin determines their wide range of biological effects. Phytochemicals include substances with antioxidant, antimicrobial, antilabmitic, antidiabetic, antiallergic, antiviral, and anticancer activity [6, 7, 8, 9, 10, 11, 12, 13]. These compounds, in their native form, are often characterized by poor solubility in an aqueous environment, which limits their bioavailability. On the other hand, they have low toxicity, which allows for the administration of higher doses. Compounds of natural origin may be an alternative in the treatment of resistant cancers and may also be used in combination therapy. Efficacy and the probability of complications and side effects are the basic parameters in therapy selection [14]. The increase in interest in phytochemicals and the decrease in the share of synthetic substances in anticancer agents results from the failure of completely synthetic products to achieve therapeutic effects and the occurrence of drug resistance [15]. Examples of compounds of plant origin with high therapeutic potential include Apomorphine, used in [PERSON]'s disease, isolated from _Papaver somifierum_ L., and the antimalarial drug Arteether, a semi-synthetic derivative of artemisinin obtained from the species _Artemisia annua_. The alkaloid Galantamine isolated from _Galanthus woronowui_ has been used to treat symptoms of [PERSON]'s disease. Research on phytochemicals for anticancer efficacy has led to the discovery of paclitaxel (isolated from _Taxus brevifolia Nutt._), commonly used in the treatment of ovarian, breast, and non-small-cell lung cancer (Figure 1) [16; 17]. Pytochemicals and derivatives obtained from them are currently a promising source of obtaining new anticancer drugs that can effectively improve the treatment of cancer patients and reduce side effects related to chemotherapy [16]. Much attention has been paid in recent years to the study of pentacyclic triterpenoids of the lupane type. Betulin, which belongs to this group of derivatives, was first isolated almost 250 years ago from birch bark [18]. Currently, numerous studies have confirmed that this compound has a wide spectrum of biological activity (anticancer, antiviral, antibacterial, and others). The structure of betulin, composed of four six-membered rings and one five-membered ring, also contains two hydroxyl groups at the C3 and C28 positions and an isopropenyl moiety at carbon 19. Structural changes at the mentioned positions obtained by chemical synthesis or biotransformation enable the transformation of betulin into derivatives with anticancer potential [19; 20; 21]. Isolated from liver by [PERSON] in 1951, \(\alpha\)-lipoic acid is an endogenous organosulfur compound synthesized de novo in mitochondria. The substrates for de novo synthesis of \(\alpha\)-lipoic acid in the body are fatty acids and cysteine. This process takes place in the liver and other tissues, but it is not efficient enough to meet the energy needs of the cell, so this compound must also be supplied to the body from exogenous sources. A significant amount of \(\alpha\)-lipoic acid is found in green vegetables such as spinach and broccoli.