Academic literature on the topic 'Vinblastine, vincristine, vinca alkaloids'

The periwinkle-derived alkaloids vinblastine 2a and vincristine 2b are still mainstays of cancer chemotherapy. The more complex half of these dimeric alkaloids, vindoline 1, presents a formidable challenge for total synthesis. Building on his previous work (Organic Lett. 2005, 7, 4539), Dale L. Boger of Scripps/La Jolla devised (J. Am. Chem. Soc. 2010, 132, 3685) a strikingly simple solution to this problem based on sequential cycloaddition. The starting point for the synthesis was the ester 3, derived from D-asparagine. This was extended to 4, condensation of which with 5 gave the enol ether 6. On heating, 7 cyclized to 8, which lost N2 to give the zwitterion 9. Addition of the intermediate 9 to the indole then gave 10. In one reaction, the entire ring system of vindoline, appropriately oxygenated, was assembled, with the original stereogenic center from D-asparagine directing the relative and absolute configuration of the final product. To complete the synthesis, the pendant carbon on 11 had to be incorporated into the pentacyclic skeleton. After adjusting the relative configuration of the secondary alcohol, the N was rendered nucleophilic by reduction of the amide to the amine. Oxidation delivered 14, which on activation as the tosylate smoothly rearranged to the ketone 15. Reduction and regioselective dehydration then completed the synthesis of vindoline 1.

Great strides had been made in the war against cancer with chemotherapy even before the emergence of protein kinase inhibitors. For instance, prior to vinblastine (1, Velban) became available in 1964 for the treatment of lymphoma, the diagnosis of Hodgkin’s disease (a cancer of the lymph nodes) was virtually a death sentence. Today there is a 90% chance of survival with the treatment by vinca alkaloids such as 1 and other chemotherapies. Similarly, when Sidney Farber discovered the effects of methotrexate (2, Trexall) on leukemia, it marked the beginning of the triumph over childhood leukemia. Following Barnett Rosenberg’s discovery of cisplatin (3, Platinol)’s effects on tumor cells in 1967, cisplatin and its analogs such as carboplatin (4, Paraplatin) and oxaliplatin (5, Eloxatin) contributed significantly in boosting the survival rate of patients with metastatic testicular cancer, ovarian tumors, and bladder cancer. Most significantly, breast cancer, a malady striking one in eight women, has been effectively managed via a plethora of treatments including surgery, radiation, and chemotherapies. The arsenal of chemotherapeutics for treating breast cancer includes SERMs such as tamoxifen (6) and raloxifene (7, Evista). Type I, II, and III aromatase inhibitors have now also been widely prescribed to combat breast cancers (more details may be found in chap. 4). Today, breast cancer is sometimes viewed as a chronic disease that can be managed, rather than a lethal disease. Despite the efficacy of the aforementioned chemotherapeutics, they kill cancer cells and normal cells with equal ferocity. (Some have compared chemotherapy to a “carpet bombing” strategy.) However, the reason these chemotherapies are effective is that cancer cells divide at much faster rate than normal cells; therefore, chemotherapies kill more malignant cells than healthy cells. Chemotherapies invariably come with significant side effects rooted. For example, hair follicle cells have a physiologically high mitosis rate; therefore, chemotherapies kill them faster than other healthy cells. In the same vein, other common side effects of chemotherapy include diarrhea (because ephithelial renewal is inhibited), bone marrow suppression (because granulopoiesis, thrombopoiesis, cytopoiesis, and erythropoiesis are inhibited), and lymph node damage (because of lymphocyte multiplication inhibition causes immune weakness).