Semi-Synthetic Analogues of Cryptolepine as a Potential Source of Sustainable Drugs for the Treatment of Malaria, Human African Trypanosomiasis, and Cancer.
Semi-Synthetic Analogues of Cryptolepine as a Potential Source of Sustainable Drugs for the Treatment of Malaria, Human African Trypanosomiasis, and Cancer.
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DOI：
10.3389/fphar.2022.875647
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发表时间：
2022
影响因子：
5.6
通讯作者：
Wright, Colin W.
中科院分区：
文献类型：
--
作者：
Abacha, Yabalu Z.;Forkuo, Arnold Donkor;Gbedema, Stephen Y.;Mittal, Nimisha;Ottilie, Sabine;Rocamora, Frances;Winzeler, Elizabeth A.;van Schalkwyk, Donelly A.;Kelly, John M.;Taylor, Martin C.;Reader, Janette;Birkholtz, Lyn-Marie;Lisgarten, David R.;Cockcroft, Jeremy K.;Lisgarten, John N.;Palmer, Rex A.;Talbert, Rosemary C.;Shnyder, Steven D.;Wright, Colin W.
关键词：
面对寄生虫对抗疟疾药物耐药性的增加，根除疟疾的前景仍然具有挑战性，因此迫切需要有效对抗无性、有性和肝期疟疾寄生虫的新型抗疟疾药物。此外，新的抗疟疾药物需要负担得起，最有需要的人可以获得，并且考虑到气候变化，理想情况下应该是可持续的。西非攀援灌木Cryptolepis sanguinolenta传统上用于治疗疟疾；其主要生物碱--隐孢子碱(1)已被证明具有抗疟疾特性，合成类似物2，7-二溴隐孢子碱(2)是开发新抗疟疾药物的先导。隐甲素(1)的分离是通过两步索氏提取血根素，然后结晶(产率0.8%，以干燥的根计)。1与N-溴或N-碘代丁二酰亚胺在三氟乙酸中反应，以较高的产率合成了7-溴-(3)，7，9-二溴-(4)，7-碘-(5)和7，9-二溴隐烷(6)。所有化合物在体外都有抗疟活性，但有6个化合物对Hep G2细胞具有最高的选择性：恶性疟原虫(氯喹抗性株K1)，IC50=0.25µM，SI=113；晚期，配子体，IC50=2.2µM，SI=13；肝期，伯氏疟原虫子孢子IC50=6.13µM，SI=4.6。化合物3-6对新出现的人畜共患病物种诺氏假单胞菌也有活性，其中5的活性最强(IC50=0.11µM)。此外，3-6在NM浓度下对布氏毛滴虫有较强的抑制作用，且选择性较好，其中6的选择性最强(IC50=59 nM，SI=478)。这些化合物对野生型卵巢癌细胞以及对阿霉素耐药的卵巢癌细胞和顺铂耐药的卵巢癌细胞也具有细胞毒性。在小鼠急性经口毒性试验中，3-6在高达100 mg/kg/剂量×3天的剂量下没有表现出毒性作用。这项研究表明，血吸虫可以作为一种可持续的新化合物来源，可能导致开发治疗疟疾、非洲锥虫病和癌症的新药物。
The prospect of eradicating malaria continues to be challenging in the face of increasing parasite resistance to antimalarial drugs so that novel antimalarials active against asexual, sexual, and liver-stage malaria parasites are urgently needed. In addition, new antimalarials need to be affordable and available to those most in need and, bearing in mind climate change, should ideally be sustainable. The West African climbing shrub Cryptolepis sanguinolenta is used traditionally for the treatment of malaria; its principal alkaloid, cryptolepine (1), has been shown to have antimalarial properties, and the synthetic analogue 2,7-dibromocryptolepine (2) is of interest as a lead toward new antimalarial agents. Cryptolepine (1) was isolated using a two-step Soxhlet extraction of C. sanguinolenta roots, followed by crystallization (yield 0.8% calculated as a base with respect to the dried roots). Semi-synthetic 7-bromo- (3), 7, 9-dibromo- (4), 7-iodo- (5), and 7, 9-dibromocryptolepine (6) were obtained in excellent yields by reaction of 1 with N-bromo- or N-iodosuccinimide in trifluoroacetic acid as a solvent. All compounds were active against Plasmodia in vitro, but 6 showed the most selective profile with respect to Hep G2 cells: P. falciparum (chloroquine-resistant strain K1), IC50 = 0.25 µM, SI = 113; late stage, gametocytes, IC50 = 2.2 µM, SI = 13; liver stage, P. berghei sporozoites IC50 = 6.13 µM, SI = 4.6. Compounds 3–6 were also active against the emerging zoonotic species P. knowlesi with 5 being the most potent (IC50 = 0.11 µM). In addition, 3–6 potently inhibited T. brucei in vitro at nM concentrations and good selectivity with 6 again being the most selective (IC50 = 59 nM, SI = 478). These compounds were also cytotoxic to wild-type ovarian cancer cells as well as adriamycin-resistant and, except for 5, cisplatin-resistant ovarian cancer cells. In an acute oral toxicity test in mice, 3–6 did not exhibit toxic effects at doses of up to 100 mg/kg/dose × 3 consecutive days. This study demonstrates that C. sanguinolenta may be utilized as a sustainable source of novel compounds that may lead to the development of novel agents for the treatment of malaria, African trypanosomiasis, and cancer.
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影响因子：
3
作者：
Forkuo AD;Ansah C;Mensah KB;Annan K;Gyan B;Theron A;Mancama D;Wright CW
通讯作者：
Wright CW
DOI：
10.1007/978-3-030-64853-4_4
发表时间：
2021-01-01
影响因子：
--
作者：
Shnyder, Steven D;Wright, Colin W
通讯作者：
Wright, Colin W
影响因子：
3.6
作者：
Taylor, Martin C.;McLatchie, Alex P.;Kelly, John M.
通讯作者：
Kelly, John M.
影响因子：
16.6
作者：
Reader J;van der Watt ME;Taylor D;Le Manach C;Mittal N;Ottilie S;Theron A;Moyo P;Erlank E;Nardini L;Venter N;Lauterbach S;Bezuidenhout B;Horatscheck A;van Heerden A;Spillman NJ;Cowell AN;Connacher J;Opperman D;Orchard LM;Llinás M;Istvan ES;Goldberg DE;Boyle GA;Calvo D;Mancama D;Coetzer TL;Winzeler EA;Duffy J;Koekemoer LL;Basarab G;Chibale K;Birkholtz LM
通讯作者：
Birkholtz LM
影响因子：
4.5
作者：
Ansah, C;Khan, A;Gooderham, NJ
通讯作者：
Gooderham, NJ