Camptothecin, referred to as CPT, is a natural product, and its chemical structure contains an oxygen-containing aromatic ring and a hydrophilic monocyclic tetraazine benzofuran ring. CPT is a compound with important biological activity. It has been found to have significant anticancer activity and is a very important anticancer drug. However, the natural sources of CPT are very scarce, and whether CPT can be obtained through chemical synthesis without the limitation of natural sources has always been a hot issue of concern to researchers. This paper systematically expounds all the synthesis methods of CPT at present.
1. Natural source synthesis:
CPT was first isolated from the commercial southern fern Camptotheca acuminata. The CPT content of this plant is very low, so natural sources are extremely limited. In addition, other plants and microbes have also found CPT-containing organisms, but in more rare and lower quantities.
2. Separately synthesize CPT:
Due to the very limited supply of CPT from natural sources, researchers have investigated various methods to artificially prepare CPT.
(1) Gilbert synthesis
In 1966, Gilbert first reported the method of synthesizing CPT by reacting p-methoxyphenethylamine with β-keto acid or its ester through ring closure reaction. This reaction produces an intermediate called 2-(2-methoxyethoxy)ethylisoxazole (EAO), which can be condensed to form CPT.
(2) Fukuyama synthesis
In 1996, Fukuyama proposed a new synthetic method to prepare CPT by using a strong electrophilic fluoride ion reagent and a dianthrone derivative as reactants. In the early stage of the reaction, the primary amine protecting group is removed by decomposition to generate the enol of the terminal unsaturated bond, thereby inducing the CPT to obtain the synthesis of the polycyclic system.
(3) Mannich synthesis
In 2002, Kuehne and Hofheinz^ synthesized CPT by the Mannich reaction, which uses catechol and diaryl ketone and formaldehyde as reactants, and uses acid as catalyst.
(4) Moura-Letts synthesis
In 2015, Moura-Letts prepared CPT by Mannich and Diels-Alder reaction using piperidine acetate hydrochloride and other reactants.
3. Semi-synthetic CPT:
Semi-synthetic CPT uses CPT derivatives as starting materials and undergoes different chemical transformations to produce potentially active CPT derivatives. Semi-synthetic CPT has a wealth of variation possibilities and is a commonly used method in organic synthesis.
(1) Topotecan and Irinotecan
Of the semi-synthetic CPTs, Topotecan and Irinotecan are best known. These two compounds will be further contradicted to produce a derivative SN-38, which has potential activity in the treatment of cancer. These compounds generate different molecular structures through different substitutions on the 2'-hydroxyethyl and 10-acyl groups. In medical treatment, Topotecan and Irinotecan have been proven to be effective drugs in the treatment of ovarian cancer and colorectal cancer.
(2) 4α-hydroxy CPT
4α-Hydroxy CPT is a CPT synthesized by a semi-synthetic method. The first modification of CPT is to add a hydroxyl group to the 4-position. This compound has lower toxicity, is easier to handle, and is easier to crystallize at low concentrations.
(3) 10-(N,N-Dimethylamino) CPT
In 1969, Chen and two other research groups respectively reported a saturated CPT derivative, 10-(N,N-dimethylamino)CPT. The derivative has greater water solubility and stronger bioavailability, and has better therapeutic effect compared with CPT.
4. Other synthetic methods:
There are some other methods of synthesizing CPT such as: Kuehne synthesis (from Regina Kuehne and Hiller), Friedländer synthesis (first reported by Hans Friedländer), linear synthesis and some others. Since these methods are not specific enough, we will not describe them.
In summary, all current synthetic methods on CPT have been systematically summarized and their respective advantages and disadvantages are provided. Although the supply of CPT from natural sources is limited, through various chemical methods, a large number of CPT derivatives can be synthesized, which is expected to provide better options for anticancer therapy.
Camptothecin is a special toxin alkaloid with a wide range of anti-tumor pharmacological effects, especially in liver cancer, gastric cancer, lung cancer, ovarian cancer, leukemia and other aspects. Its anti-tumor mechanism is mainly through inhibiting the activity of topoisomerase I (Top1), so that the DNA of tumor cells cannot be replicated, resulting in the death of tumor cells.
In addition, Camptothecin also has an immunomodulatory effect, which can regulate the functions of immune cells such as T and B lymphocytes and macrophages, and enhance the body's immunity.