Topoisomerases are interesting targets for drug discovery. In the present study, we attached saturated carbon atoms to the 10-position of camptothecin and synthesized 10 new camptothecin derivatives from 10-HCPT or SN-38. The activities of new compounds were evaluated both in vitro and in vivo. The most promising compound F10, 7-ethyl-10-(2-oxo-2-(piperidin-1-yl)ethoxy)camptothecin, inhibited cancer cells growth with the IC₅₀ of 0.002, 0.003, 0.011 and 0.081 μM on Raji, HCT116, A549 and Lovo cells, respectively. Meanwhile, oral administration of F10 remarkably suppressed the HCT116-xenograft tumor growth in the nude-mice model at the dosage of 0.5, 2.0 and 8.0 mg/kg in vivo. Intraperitoneal administration of F10 can completely inhibit Raji-xenograft tumor growth in established NPG mouse model at 2.0 and 4.0 mg/kg. In addition, the minimum lethal doses of F10 and SN-38 in mice by intravenous administration were 80 and 40 mg/kg (or 0.155, 0.102 mmol/kg), respectively. The solubility of F10 reached 9.86 μg/mL in a buffer solution of pH 4.5. The oral bioavailability of F10 achieved 22.4% in mice. The molecular docking model revealed that F10 can interact with topoisomerase I-DNA complex. Our findings indicate that F10 is a new orally-oavailable antitumor agent with potent anticancer effect. Furthermore, attaching a ring hydrophobic moiety to the 10-position of camptothecin provides a favorable approach in the optimization of camptothecin.

拓扑异构酶是药物发现的有趣靶标。在本研究中，我们将饱和碳原子连接到喜树碱的10位上，并从10-HCPT或SN-38合成了10个新的喜树碱衍生物。在体外和体内评估了新化合物的活性。最有希望的化合物F10 7-乙基-10-（2-氧代-2-（哌啶-1-基）乙氧基）喜树碱可抑制癌细胞生长，在Raji上的IC ₅₀为0.002、0.003、0.011和0.081μM。 HCT116，A549和Lovo细胞。同时，在体内以0.5、2.0和8.0mg / kg的剂量口服F10在裸鼠模型中显着抑制了HCT116-异种移植肿瘤的生长。腹膜内给予F10可以在已建立的NPG小鼠模型中以2.0和4.0 mg / kg完全抑制Raji-异种移植肿瘤的生长。另外，通过静脉内施用在小鼠中的F10和SN-38的最小致死剂量分别为80和40mg / kg（或0.155，0.102mmol / kg）。F10在pH 4.5的缓冲溶液中的溶解度达到9.86μg/ mL。F10在小鼠中的口服生物利用度达到22.4％。分子对接模型表明F10可以与拓扑异构酶I-DNA复合物相互作用。我们的发现表明F10是一种新型的口服抗肿瘤药，具有有效的抗癌作用。此外，将环疏水部分连接到喜树碱的10位上为喜树碱的优化提供了一种有利的方法。