Alkaloid, vinca

Various strategies to increase alkaloids levels, including adjusting the medium, temperature, light, and aeration, have been reviewed [38, 39]. Many plant phytohormones and ehcitors, both biotic and abiotic, have been applied to increase alkaloids accumulation [29, 39]. Several studies showed that MeJA, ethylene, and fungal ehcitors individuahy or conjointly promoted vindohne accumulation in 

STR strictosidine synthase SGD strictosidine -D-glucosidase 6,7E 6,7-epoxidase 19H 19-hydroxylase MAT minovincinine 19-hydroxy-O-acetyltransferase T16H tabersonine 16-hydroxylase 160MT 16-hydroxytabersonine-O-methyltransferase T30/T3R tabersonine 3-oxygenase 

As mentioned earlier, C. roseus suspension cells and hairy roots do not produce anticancer drugs mainly because the vindoline pathway is blocked in those two systems. Through intricate manipulation of several elicitors of the vindoline pathway and inhibitors of the bypass, vindoline and vinblastine were produced in suspension cells as determined by HPLC [41]. The highest vinblastine yield of 810pgg DW was reported, which was much higher than that in the mature plant (12pgg DW). However, this report would be strengthened if additional evidence could be provided to support that the vindoline biosynthetic pathway is active in suspension cell cultures, such as the NMR and MS/MS data of vindoline and transcription levels of all the enzymes in the vindoHne pathway. 

Heterologous expression of the TIA synthetic pathway in non-native plant hosts and microbial hosts is under development and will potentially pave the way for producing interesting TIA from hosts that grow faster and are easier to be cultured. Most of the heterologous expression efforts are focused on 

Hosts Engineering strategies Role in TIA pathway Expression system Main observations 

When dissolved in superacidic media, complex molecules such as steroids or alkaloids undergo polyprotonation of reasonably distant functions. This prevents the degradation generally observed under usual strong acidic conditions. Moreover, the lack of basic or nucleophilic entities in the medium avoids further processes 

Vinflunine (Javlor ) is a member of the second-generation Vinca dimer alkaloids. This 4 -difluoro analogue is more active than vinorelbine in several cancers. It is now in Phase III clinical trials as a chemotherapeutic agent targeted at a variety of cancers (non-small-cell lung and bladder cancers). However, the role of fluorine substitu- 

During studies on the synthesis on vinca alkaloids and related compounds it was found that (-)-criocerine 1 and a number of analogues underwent smooth dimerisation when dissolved in acetic acid at room temperature for 24 hours. Thus, 1 gave 2 in 86% yield. 

Dubrovay et al. reported a study of the Vinca alkaloids vinblastine and vincristine in 2013 that included chemical shift data for vinblastine (38) and vincristine (39) and their mono- and disalts in several solvent systems (see Table 4) [56]. The authors also reported extensive MS/MS data in the study of these complex alkaloids. 

Position CDCU DMSO CDsCN-HDaO 1 1 DMSO CDCI3 DMSO CD3CN3-D20 1 1 

Position CDCI3 DMSO CDsCN-hDjO 1 1 DMSO CDCI3 DMSO CD3CN+D2O 1 1 

Vincristine has been measured using an ODS-modified silica analytical column with acetonitrile-methanol-aq. phosphate buffer (25mmolL pH 7.0) (20 4-48-1- 32) as eluent and ED (GCEs, -1-0.75 V or -t-0.83 V, vs Ag/AgCl).  

Sample preparation was by column switching using a pellicular ODS-modified silica preconcentration column. Vinblastine was the internal standard. The LoD was 0.3pgL (1.2 mL sample). Koopmans et al7 developed an automated method for vincristine using column switching. Both the preparation and analytical columns were based on ODS-modified silica. The eluent was acetonitrile-methanol-aq. phosphate buffer (20 mmol L pH 7.0) (15 -H 50 -f- 35). The GCE was operated at -1-0.83 V vs Ag/AgCl. The LLoQ (0.3 mL sample) was 0.48 pgL (RSD= 10.3%). Vinblastine was the internal standard. When the method was applied to the assay of vincristine in mononuclear cells from children with acute lymphoblastic leukaemia the LLoQ was 1.17pgL (RSD = 5.7%).  

---

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

Vinpocetine (2), another dmg initially categorized as a cerebral vasodilator, is a member of the vinca alkaloid family of agents (7). However, interest in this compound as a potential dmg for learning and memory deficits comes from its abiUty to act as a neuronal protectant. This compound was evaluated in 15 patients with AD over a one-year period and was ineffective in improving cognitive deficits or slowing the rate of decline (8). However, in studies of patients with chronic vascular senile cerebral dysfunction (9) and organic psycho syndrome (10), vinpocetine showed beneficial results. 

Vindoline [2182-14-1] (45), a monomeric Vinca alkaloid intermediate important in the synthesis of antineoplastic alkaloids, is selectively converted in good yield to 0-desmethylvindoline [68687-22-9] (46) by cultures of Sepedonium chrysospermum (17,25), whereas Streptomyces albogriseolus removes only the A[-methyl group to give (47) (91) (see Chemotherapeutics, anticancer). 

In addition to the Vinca alkaloids and taxol, a limited number of other cytotoxic agents have been demonstrated to act at the level of tubulin. This... 

Vinca alkaloids (vincristine, vinblastine, vindesine) are derived from the periwinkle plant (Vinca rosea), they bind to tubulin and inhibit its polymerization into microtubules and spindle formation, thus producing metaphase arrest. They are cell cycle specific and interfere also with other cellular activities that involve microtubules, such as leukocyte phagocytosis, chemotaxis, and axonal transport in neurons. Vincristine is mainly neurotoxic and mildly hematotoxic, vinblastine is myelosuppressive with veiy low neurotoxicity whereas vindesine has both, moderate myelotoxicity and neurotoxicity. 

Ngan VK, Bellman K, Hill BT et al (2001) Mechanism of mitotic block and inhibition of cell proliferation by the semisynthetic Vinca alkaloids vinorelbine and its newer derivative vinflunine. Mol Pharmacol 60 225-232... 

Vinca alkaloids are derived from the Madagascar periwinkle plant, Catharanthus roseus. The main alkaloids are vincristine, vinblastine and vindesine. Vinca alkaloids are cell-cycle-specific agents and block cells in mitosis. This cellular activity is due to their ability to bind specifically to tubulin and to block the ability of the protein to polymerize into microtubules. This prevents spindle formation in mitosing cells and causes arrest at metaphase. Vinca alkaloids also inhibit other cellular activities that involve microtubules, such as leukocyte phagocytosis and chemotaxis as well as axonal transport in neurons. Side effects of the vinca alkaloids such as their neurotoxicity may be due to disruption of these functions. 

Vincristine and vinblastine (vinca alkaloids) comprise another class of drugs that inhibit the polymerization of microtubules but do so by binding to the tubulin molecule at a site different from the colchicine site. Cultured cells exposed to high concentrations of vinca alkaloids develop intracytoplasmic paracrystalline aggregates of tubulin. These drugs are employed clinically in cancer chemotherapy to inhibit the growth of tumors composed of rapidly dividing cells. 

Another drug is taxol, which is extracted from the bark of the Pacific yew tree, Taxus brevijolia. Unlike colchicine and the vinca alkaloids, taxol binds tightly to microtubules and stabilizes them against depolymerization by Ca. It also enhances the rate and yield of microtubule assembly, thereby decreasing the amount of soluble tubulin in the cytosol pool. Again, the overall effect of taxol is to arrest dividing cells in mitosis. Taxol is used in cancer chemotherapy. 

Certain drugs bind to microtubules and thus interfere with their assembly or disassembly. These include colchicine (used for treatment of acute gouty arthritis), vinblastine (a vinca alkaloid used for treating certain types of cancer), paclitaxel (Taxol) (effective against ovarian cancer), and griseoflilvin (an antifungal agent). 

The periwinkle, or vinca plant, served as a source for the drugs vincristine and vinblastine, which are commonly referred to as the vinca alkaloids. The vinca alkaloids inhibit the assembly... 

Vinblastine is another vesicant vinca alkaloid that causes myelo-suppression and less neurotoxicity than vincristine. The pharmacokinetics of vinblastine are best described by a three-compartment model, with an a half-life of 25 minutes, a 3 half-life of 53 minutes, and a terminal half-life of 19 to 25 hours.12 Vinblastine has shown activity in the treatment of bladder, breast, and kidney cancer, as well as some lymphomas. The doses of vinblastine tend to be higher on a milligram per meter squared basis than vincristine. Nausea and vomiting are minimal with vinblastine. Other side effects include mild alopecia, rash, photosensitivity, and stomatitis. 

Vinca alkaloids Vinorelbine Myelosuppression Fatigue, nausea, vomiting, ulceration necrosis with extravasation... 

Anthracycline, mechlorethamine, and vinca alkaloid extravasations typically cause immediate pain. 

Non-DNA-binding agents include the vinca alkaloids and etoposide. These agents tend to cause injury in the pattern of a thermal burn and are cleared more easily from interstitial spaces. Thus they are more readily neutralized and tend to have a better healing prognosis. 

If extravasation occurs, the infusion should be stopped immediately, with aspiration of fluid from the site, needle, and tubing as much as possible. The affected limb or area should be elevated (if possible). The site should be documented photographically as well as the time, date, site, patient complaints, and estimated volume of extravasated drug.36 Both hot and cold packs have been used to manage extravasations, but use of the proper therapy for certain agents is critical. For example, warm compresses have been shown to worsen doxorubicin extravasations, whereas cold packs may exacerbate vinca alkaloid... 

Vinca alkaloids Hot packs Hyaluronidase Inject 1-6 mL of 150 units/mL concentration (150-900 units) through IV line or SQ if removed may repeat every 3-4 hours if needed Dilute with normal saline. 

Hyaluronidase is the antidote of choice for vinca alkaloid and high-concentration epipodophyllotoxin extravasations. Hyaluronidase breaks down hyaluronic acid, which functions as tissue cement. This promotes absorption of the extravasated drug away from the local site. Hyaluronidase also may be used for paclitaxel extravasations, but there are conflicting reports regarding its efficacy.39 Hyaluronidase should not be used with anthracycline extravasations because enhancement of local spread may occur. 

Examples of inhibitors of chromatin function derived from flowering plants (Fig. 80) are etoposide (lignan) and alkaloids camptothecin, Vinca alkaloids, and 7 epitaxol. The rhizome of Podophyllum peltatum L. (May apple, Berberidaceae) has been used to remove warts and to relieve the bowels from costiveness since very early times. It contains podophyllo-toxin, a cytotoxic lignan from which etoposide (Vepesid ), which is used to treat lung cancer, lymphomas, and leukemias on account of its ability to inhibit the activity of... 

As part of a study on the synthesis of Vinca alkaloids, the polycyclic compound 140 was prepared. Treatment of 141 with aqueous alkali gives the triheterocyclic product 142, which was isolated as its perchlorate salt. The iminium functionality of 142 can then be reduced stereospecifically by treatment with sodium borohydride <1985JOC3760> (Scheme 38). 

Vinblastine -vinca alkaloid inhibits tubulin polymerization G2 phase specific -bone marrow suppression -vesicant if extravasated -nausea and vomiting -constipation (often secondary to neuropathy induced ileus) -neuropathy (jaw pain, peripheral neuropathy, autonomic neuropathy) -SIADH -tumor pain... 

I 14. Which of the following is considered to be the effective mechanism of action of the vinca alkaloids ... 

I 14. The answer is a. (Hardman, pp 1259, 1260.) The vinca alkaloids, vincristine and vinblastine, have proved valuable because they work on a different principle from most cancer chemotherapeutic agents They (like colchicine) inhibit mitosis in metaphase by their ability to bind to tubulin. This prevents the formation of tubules and, consequently, the orderly arrangement of chromosomes, which apparently causes cell death. 

---