王 聰 梅顯貴 朱偉明

(中國(guó)海洋大學(xué)醫(yī)藥學(xué)院 海洋藥物教育部重點(diǎn)實(shí)驗(yàn)室, 青島 266003)

海洋鏈霉菌來源的天然產(chǎn)物*

王 聰 梅顯貴 朱偉明①

(中國(guó)海洋大學(xué)醫(yī)藥學(xué)院 海洋藥物教育部重點(diǎn)實(shí)驗(yàn)室, 青島 266003)

海洋鏈霉菌(Streptomyces spp.)由于其獨(dú)特的生理和代謝功能, 成為海洋微生物活性物質(zhì)的主要來源。對(duì)2010～2013年初的海洋放線菌天然產(chǎn)物的統(tǒng)計(jì)表明, 研究最多的放線菌是鏈霉菌, 占海洋放線菌新天然產(chǎn)物的 60%。本文綜述了自 1976年第一個(gè)海洋鏈霉菌天然產(chǎn)物到2016年6月的40年間報(bào)道的547個(gè)海洋鏈霉菌天然產(chǎn)物的結(jié)構(gòu)、生物活性及其微生物來源。其結(jié)構(gòu)包括含氮化合物(如生物堿)、聚酮、萜類、甾體等, 其中含氮化合物是其主要類型, 占海洋鏈霉菌天然產(chǎn)物總數(shù)的 61%; 而 67%的海洋鏈霉菌天然產(chǎn)物表現(xiàn)出細(xì)胞毒、抑菌、抗瘧和抗寄生蟲等生物活性。

海洋放線菌; 鏈霉菌; 天然產(chǎn)物; 來源; 結(jié)構(gòu); 生物活性

海洋鏈霉菌由于其獨(dú)特的生理和代謝功能, 成為海洋微生物活性天然產(chǎn)物的重要來源。本實(shí)驗(yàn)室對(duì)2010～2013年初海洋放線菌新天然產(chǎn)物的統(tǒng)計(jì)表明, 海洋放線菌研究最多的是鏈霉菌(Streptomyces), 占海洋放線菌新天然產(chǎn)物的60%(趙成英等, 2013)。海洋鏈霉菌新天然產(chǎn)物的研究始于1976年, Okami 課題組報(bào)道了首例海洋鏈霉菌天然產(chǎn)物 aplasmomycins A-C (150～152)(Okami et al., 1976); 截至2016年6月的40年時(shí)間里, 已報(bào)道了547個(gè)海洋鏈霉菌新天然產(chǎn)物。這些天然產(chǎn)物的結(jié)構(gòu)類型包括生物堿、聚酮、萜類、甾體、鹵代物、聚醚類等; 并具有多種生物活性, 包括抗腫瘤、抗菌、抗瘧和抗寄生蟲等。因此, 海洋鏈霉菌天然產(chǎn)物可能是發(fā)現(xiàn)藥物先導(dǎo)化合物的重要的資源寶庫(kù), 本文將從海洋鏈霉菌的來源出發(fā), 綜述這些天然產(chǎn)物的結(jié)構(gòu)及其生物活性。

1 海洋動(dòng)物來源的海洋鏈霉菌天然產(chǎn)物

1.1 海綿來源的海洋鏈霉菌天然產(chǎn)物

海綿來源的(下同)鏈霉菌Streptomyces sp. Ni-80代謝產(chǎn)生urauchimycins A(1)和B(2), 兩個(gè)化合物在 10μg/mL時(shí)具有抑制白色念珠菌(Canidia albicans)活性(Imamura et al., 1993)。Streptomyces sp. KM86-9B代謝產(chǎn)生具有拓?fù)洚悩?gòu)酶 I抑制活性的化合物 3～9 (Lee et al., 1998)。環(huán)肽 dehydroxynocardamine (10)和desmethylenylnocardamine (11)來自Streptomyces sp. M1087, 具有微弱的重組酶sortase B抑制活性, EC50分別為88.3μg/mL和126.4μg/mL (Lee et al., 2005)。Streptomyces sp. HB202代謝產(chǎn)生吩嗪類化合物streptophenazines A–H (12～19), 化合物12、14～16和19對(duì)枯草芽胞桿菌(Bacillus subtilis)的最小抑菌濃度(minimum inhibitory concentration, MIC)分別為46.9μg/mL、15.6μg/mL、62.5μg/mL、62.5μg/mL和15.6μg/mL, 化合物 12～14、17和 18對(duì)金黃色葡萄球菌(Staphylococcus aureus)的 MIC分別為62.5μg/mL、62.5μg/mL、46.9μg/mL、62.5μg/mL和62.5μg/mL(Mitova et al., 2008)。Streptomyces sp. SpC080624SC-11代謝產(chǎn)生3個(gè)吩嗪類化合物20～22(Izumikawa et al., 2010b), Streptomyces sp. Sp080513GE-23代謝產(chǎn)生 2個(gè)含有氯代吲哚單元的二肽類化合物 23和24(Motohashi et al, 2010c), Streptomyces sp. NBRC105896代謝產(chǎn)生化合物 25、對(duì)人宮頸癌 Hela細(xì)胞和惡性胸膜間皮瘤細(xì)胞 ACCMESO-1的IC50分別為49μmol/L和88μmol/L (Izumikawa et al., 2010a), Streptomyces sp. Sp080513GE-26產(chǎn)生 2個(gè)新的蒽環(huán)類化合物26和27、化合物26對(duì)Hela細(xì)胞和HL-60細(xì)胞的 IC50分別為 120μmol/L和 210μmol/L (Motohashi et al., 2010a)。Streptomyces sp. SpD081030ME-02代謝產(chǎn)生水楊酰胺衍生物28, 對(duì) Hela細(xì)胞的 IC50為 28μmol/L(Ueda et al., 2010)。聯(lián)苯蒽糖苷29來自Streptomyces sp. HB202(Schneemann et al., 2010), 化合物29對(duì)HepG2、HT-29、GXF251L、LXF529L等8種人腫瘤細(xì)胞的 IC50為 0.13～0.33μmol/L, 對(duì)鼠成纖維細(xì)胞NIH-3T3的IC50為0.22μmol/L, 且對(duì)包括耐甲氧西林金黃色葡萄球菌、表皮葡萄球菌(Staphylococcus epidermidis)、人皮膚桿菌和痤瘡丙酸桿菌(Propionibacterium acnes)等9種細(xì)菌的IC50為2.5～8.4μmol/L。Tetromycins化合物30～33產(chǎn)自鏈霉菌S. axinellae Pol001T,可以抑制布氏錐蟲(Trypanosoma bruce) (Pimentel-Elardo et al., 2011)?；衔風(fēng)obophorins C (34)和D (35)產(chǎn)自肉質(zhì)鏈霉菌S. carnosus AZS17,化合物34和35對(duì)人肝癌細(xì)胞株7402的IC50分別為0.6μg/mL和723.1μg/mL、對(duì)人乳腺癌細(xì)胞株MDA-MB-435的IC50分別為61.8μmol/L和7.5μmol/L(Wei et al., 2011)。細(xì)黃鏈霉菌(S. microflavus)代謝產(chǎn)生 3-乙酰基-5-甲基-2′-脫氧尿嘧啶 36(Li et al., 2011); Streptomyces sp. SpD081030SC-03代謝產(chǎn)生小肽JBIR-56 (37)和JBIR-57 (38) (Motohashi et al., 2011)。吲哚生物堿 streptomycindole (39)產(chǎn)自鏈霉菌Streptomyces sp. DA22, 對(duì) HL-60、結(jié)腸癌HCT-116、卵巢上皮性癌HO-8910和人肝癌細(xì)胞HepG2沒有活性(Huang et al., 2011)。3個(gè)曲古抑菌素 40～42是鏈霉菌 Streptomyces sp. RM72的代謝產(chǎn)物, 對(duì)組蛋白脫乙?；窰DAC1的 IC50分別為 48μmol/L、74μmol/L和 57μmol/L(Hosoya et al., 2012)。環(huán)脂肽43～46產(chǎn)自Streptomyces sp. RV15 (Abdelmohsen et al., 2012); 苯并蒽醌糖苷 47～49產(chǎn)自Streptomyces sp. BCC45596 (Supong et al., 2012),其對(duì)瘧原蟲的IC50為0.053μg/mL、0.142μg/mL和 2.93μg/mL, 對(duì)結(jié)核桿菌的 MIC分別為3.13μg/mL、12.50μg/mL和6.25μg/mL, 化合物47對(duì)KB、MCF-7、NCl-H187和Vero細(xì)胞的IC50分別為0.179μg/mL、0.196μg/mL、0.092μg/mL和 1.71μg/mL, 化合物 48對(duì) KB、MCF-7、NCl-H187和 Vero細(xì)胞的 IC50分別為0.324μg/mL、0.45μg/mL、0.242μg/mL和3.05μg/mL,化合物49對(duì)KB、MCF-7、NCl-H187和Vero細(xì)胞的 IC50分別為 6.96μg/mL、3.41μg/mL、3.97μg/mL和10.07μg/mL。鏈霉菌S. tateyamensis代謝產(chǎn)生化合物 JBIR-107(50)(Izumikawa et al., 2013)。吩嗪類化合物streptophenazines I-K(51～53)來自鏈霉菌Streptomyces HB202, 化合物52對(duì)磷酸二酯酶的IC50為12.0μmol/L, 化合物53對(duì)枯草芽胞桿菌、表皮葡萄球菌、磷酸二酯酶的 IC50分別為 21.6μmol/L、14.5μmol/L和12.2μmol/L (Kunz et al., 2014)。環(huán)圈鏈霉菌S. anulatus S71代謝產(chǎn)生化合物 54(Sun et al., 2014b)。Streptomyces sp. M7_15代謝產(chǎn)生monacyclinones A-F (55～60), 化合物 57、59和60對(duì)橫紋肌肉瘤X細(xì)胞SJCRH30的IC50分別為 160μmol/L、270μmol/L和 0.73μmol/L (Vicente et al., 2015)。二肽xestostreptin (61)產(chǎn)自Streptomyces sp. S.4, 其對(duì)惡性瘧原蟲的 IC50為50μmol/L(Rakotondraibe et al, 2015)?；衔?quinomycin G (62)和環(huán)二肽 63來源于Streptomyces sp. LS298, 化合物63對(duì)ACHN、786-O、U87 MG和Jurkat腫瘤細(xì)胞的IC50分別為 0.552μmol/L、0.721μmol/L、0.627μmol/L和0.414μmol/L(Zhen et al., 2015)。Streptomyces sp. SBT345代謝產(chǎn)生氯代化合物 ageloline A (64), 對(duì)沙眼衣原體的 IC50為 9.54μmol/L (Cheng et al., 2016)。

1.2 珊瑚來源的海洋鏈霉菌天然產(chǎn)物

珊瑚來源的(下同)的鏈霉菌Streptornyces sp.代謝產(chǎn)生octalactins A (65)和B (66), 化合物65對(duì) B-16-FI0和 HCT-116細(xì)胞的 IC50分別為0.0072μg/mL和0.5μg/mL (Tapiolas et al., 1991)。多氯代聚酮 strepchloritides A (67)和B (68)產(chǎn)自Streptomyces sp. OUCMDZ-1703, 其對(duì)MCF-7 細(xì)胞的IC50分別為9.9μmol/L和20.2μmol/L(Fu et al., 2013)。Axinelline A (69)來自鏈霉菌 S. axinellae SCSIO02208, 對(duì)環(huán)氧化酶 COX-2的 IC50為2.8mmol/L(Ai et al., 2014)。Nahuoicacids 70～73來自 Streptomyces sp. SCSGAA 0027 (Nong et al., 2016)(圖1)。

圖1 化合物1～73的結(jié)構(gòu)Fig.1 Structures of compounds 1～73

1.3 其他動(dòng)物來源的鏈霉菌天然產(chǎn)物

其他海洋動(dòng)物來源的(下同)鏈霉菌 S. hygroscopicus代謝產(chǎn)生 salinamides A(74)和B(75), 其對(duì)肺炎鏈球菌Streptococcus pneumoniae的 MIC 均為 4μg/mL、對(duì)釀膿葡萄球菌(Staphylococcus pyrogenes)的 MIC 分別為4μg/mL和2μg/mL; 化合物74和75還有抗炎活性, 濃度為59μg/mL時(shí), 其對(duì)佛波醇酯誘導(dǎo)的小鼠耳水腫的抑制率分別為 84%和 83% (Trischman et al., 1994)。Halichomycin(76)來自鏈霉菌 S. hygroscopicus, 對(duì)小鼠白血病 P388細(xì)胞的 ED50為 0.13μg/mL(Takahashi et al., 1994)。大環(huán)內(nèi)酰胺aburatubolactam A (77)產(chǎn)自Streptomyces sp. SCRC-A20, 可抑制TPA誘導(dǎo)的超氧化陰離子的產(chǎn)生(Bae et al., 1996)。吲哚衍生物78～80產(chǎn)自Streptomyces sp. BL-49-58-005 (Sánchez et al., 2003), 化合物78對(duì)白血病K562細(xì)胞的GI50為8.46μmol/L; 化合物79對(duì)不同腫瘤細(xì)胞株表現(xiàn)出中等細(xì)胞毒活性, GI50在微摩爾級(jí), 并且無明顯選擇性; 化合物80對(duì)所測(cè)試的腫瘤細(xì)胞株沒有活性。粉蝶霉素piericidins C7(81)and C8(82)來自Streptomyces sp. YM14-060, 可抑制小鼠神經(jīng)母細(xì)胞瘤細(xì)胞 Neuro-2a增殖而不殺死細(xì)胞, IC50分別為0.83 nmol/L 和 0.2nmol/L (Hayakawa et al., 2007)。Streptomyces sp. JP90 代謝產(chǎn)生cinnamoylphosphoramide (83), 其對(duì)乙酰膽堿酯酶的 IC50為 250μmol/L(Quitschau et al., 2008)。Streptomyces sp. CP32的代謝產(chǎn)生噻唑類衍生物84～88, 化合物84和87可選擇性地結(jié)合 5-HT2B受體(Ki分別為 0.50μmol/L和1.54μmol/L) (Lin et al., 2010)?；衔?9產(chǎn)自Streptomyces sp. BOSC-022A(Lorente et al., 2010)。Nobilamides A-E(90～94)和F-H(95～97)分別產(chǎn)自鏈霉菌HQ696493和HQ696492, 化合物 91具有拮抗 TRPV1作用(Lin et al., 2011)?；衔?98產(chǎn)自 Streptomyces sp., 對(duì)P388細(xì)胞有細(xì)胞毒活性(Mahyudin et al., 2012)。Streptomyces sp. 1053U.I.1a.1b的代謝產(chǎn)生化合物99及其糖苷100(Lin et al., 2012)?；衔?violapyrones H (101)和 I (102)來自Streptomyces sp. 112CH148, 化合物 101對(duì)HCT-15細(xì)胞的活性最高, GI50為 1.10μg/mL (Shin et al., 2014)。聚酮類lobophorins H (103)和 I (104)產(chǎn)自 Streptomyces sp. 1053U.I.1a.3b,化合物 104對(duì)結(jié)核分枝桿菌和枯草桿菌的MIC分別為2.6mmol/L和10.6mmol/L(Lin et al., 2014)。Hyaluromycin (105)來自Streptomyces sp. MB-PO13, 化合物 105對(duì)透明質(zhì)酸酶的 IC50為14μmol/L(Harunari et al., 2014)。大環(huán)內(nèi)酯類化合物 PM100117 (106) 和PM100118 (107) 產(chǎn)自鏈霉菌 S. caniferus GUA-06-05-006A, 其對(duì) A549細(xì)胞的 GI50分別為1.3μmol/L和0.83μmol/L、對(duì)MDAMB-231細(xì)胞的 GI50分別為 2.7μmol/L和1.7μmol/L、對(duì)人結(jié)腸癌細(xì)胞 HT29 的 GI50分別為3.8μmol/L和9.2μmol/L (Pérez et al., 2016)。

2 海洋植物來源的海洋鏈霉菌天然產(chǎn)物

2.1 海藻來源的海洋鏈霉菌天然產(chǎn)物

海藻鏈霉菌Streptomyces sp. #N1-78-1代謝產(chǎn)生蒽醌類化合物 108～110, 3個(gè)化合物對(duì)金黃色葡萄球菌的 IC50分別為 0.15μmol/L、0.36μmol/L和31μmol/L(Socha et al., 2006)?；衔飐treptobactin (111)、dibenarthin (112)和tribenarthin (113)產(chǎn)自海藻鏈霉菌Streptomyces sp. YM5-799(Matsuo et al., 2011)。

2.2 紅樹林來源的海洋鏈霉菌天然產(chǎn)物

紅樹植物來源的鏈霉菌(下同) Streptomyces sp. GT2002/1503代謝產(chǎn)生吲哚并倍半萜烯xiamycin B (114)、indosespene (115)和sespenine (116), 化合物 114具有選擇性抑制 HIV活性(Ding et al., 2010)(圖2)。

圖2 化合物74～115的結(jié)構(gòu)Fig.2 Structures of compounds 74～115

Streptomyces sp. HK10552代謝產(chǎn)生化合物 117～120(Wang et al., 2010); 吲哚生物堿121和吲哚生物堿 122產(chǎn)自 Streptomyces sp. GT2002/1503, 121和 122對(duì) HT-29、GXF 251L、LXFA 629L等 12種人癌細(xì)胞的平均IC50值分別為大于 30μmol/L和 10.1μmol/L;化合物121選擇性地抑制HIV病毒的R5受體活性(Ding et al., 2010)。化合物 divergolides A-D (123～126)產(chǎn)自Streptomyces sp. HKI0576,化合物123對(duì)肺癌細(xì)胞LXFA 629L、胰腺癌細(xì)胞PANC-1、腎癌細(xì)胞RXF 486L和惡性毒瘤 Saos-2的 IC50值為 1.0～2.0μmol/L(Ding et al., 2011)。化合物divergolides A-D (127～130)也產(chǎn)自該菌(Xu et al., 2014)。鏈霉菌 S. lusitanus XM52代謝產(chǎn)生131～132, 其中132對(duì)金黃色葡萄球菌、枯草桿菌的MIC分別為32μg/mL和8μg/mL(Han et al., 2012)。倍半萜類化合物133～137產(chǎn)自放線菌Streptomyces sp. HKI0595, 對(duì) 12種人腫瘤細(xì)胞均無細(xì)胞毒活性, 對(duì)枯草桿菌和牛分支桿菌有較弱的抑制活性(Ding et al., 2012)。

2.3 其他植物來源的鏈霉菌天然產(chǎn)物

其他海洋植物來源的鏈霉菌Streptomyces sp. CANU Fox 21-2-6代謝產(chǎn)生化合物138～140, 對(duì)小鼠白血病細(xì)胞P388的IC50值為0.4～0.06μg/mL(Phipps et al., 2004)。來自草綠鹽角草(Salicornia herbacea)的鏈霉菌Streptomyces sp. FX-58代謝產(chǎn)生化合物141 (Huang et al., 2006a)和化合物142～143 (Huang et al., 2006b),化合物143對(duì)HL-60、BCTC-823和MDA-MB-435細(xì)胞的IC50值分別為6.83μg/mL、82.2μg/mL和 56.59μg/mL。黃酮類化合物 144產(chǎn)自Streptomyces sp. MA-12, 濃度為 0.25mmol/L時(shí), 對(duì)香蕉炭疽病菌、小麥赤霉病菌和桔青霉3種植物病原菌有抑制作用(Ding et al., 2013)。不飽和脂肪酸 145產(chǎn)自鏈霉菌 S. violans HTTA-F04129, 對(duì) A2780細(xì)胞的 IC50值為4.36μmol/L(Huang et al., 2014)。Streptomyces sp. LC6代謝產(chǎn)生juanlimycins A (146)和B (147), 可抑制沙門氏菌毒力島-1的分泌(Zhang et al., 2014a)。來源于滸苔的鏈霉菌Streptomyces sp. OUCMDZ- 3434代謝產(chǎn)生結(jié)構(gòu)新穎的二聚體wailupemycins H (148)和I (149), 其對(duì)α-糖苷酶的Ki值分別為16.8μmol/L和6.0μmol/L、IC50值分別為19.7μmol/L和8.3μmol/L (Chen et al., 2016)。

3 海泥和海水來源的鏈霉菌天然產(chǎn)物

3.1 海泥來源的鏈霉菌天然產(chǎn)物

海泥來源的鏈霉菌(下同)S. griseus SS-20代謝產(chǎn)生aplasmomycins A-C (150～152), 能抑制多種革蘭氏陽(yáng)性細(xì)菌(包括分枝細(xì)菌), 同時(shí)具有抗瘧原蟲的活性。感染了瘧原蟲的小鼠口服后, 瘧原蟲大大減少, 且小鼠全部存活, 而未經(jīng)過治療的小鼠在8d內(nèi)全部死亡(Okami et al., 1976; Nakamura et al., 1977)。鏈霉菌S. tenjimariensis SS-939代謝產(chǎn)生氨基糖苷類化合物istamycins A和istamycins B (153和154),對(duì)革蘭氏陽(yáng)性菌和陰性菌都有很好的抑制作用(Okami et al., 1979)。生物堿altemicidin(155)產(chǎn)自S. sioyaensis SA-1758, 具有抗腫瘤和殺螨活性(Okami et al., 1989)。4個(gè)罕見的吩嗪生物堿類化合物 156～159來自 Streptomyces sp. CNB-253, 化合物 156 對(duì)嗜血桿菌屬流感的IC50值可達(dá)到 1μg/mL、對(duì)梭菌屬產(chǎn)氣莢膜桿菌 IC50值可達(dá)到 4μg/mL(Pathirana et al., 1992)。N-乙酰-β-D-氨基葡糖苷酶抑制劑pyrostatins A (160)和B (161)產(chǎn)自Streptomyces sp. SA-3501(Aoyama et al., 1995)。二酮哌嗪maremycins A (162)和B (163)產(chǎn)自Streptomyces sp. B 9173 (Balk-Bindseil et al., 1995)。Streptomyces sp. BD-26T(20)代謝產(chǎn)生 wailupemycins A-C (164～166)和 3-epideoxyenterocin (167), 化合物167濃度在1mg/6mm disk時(shí), 對(duì)金黃色葡萄球菌的抑菌圈為 18mm; 化合物 164濃度在0.1mg/6mm disk時(shí), 對(duì)大腸桿菌E. coli 的抑菌圈為15mm (Sitachitta et al., 1996)。多色霉素 類 抗 生 素 δ-indomycinone 168 產(chǎn) 自Streptomyces sp. B 8300, 對(duì)枯草芽孢桿菌 B. subtilis的 MIC 為 100μg/mL(Biabani et al., 1997)。Actinoflavoside (169)產(chǎn)自Streptomyces sp. CNB-689, 對(duì)革蘭氏陽(yáng)性菌肺炎鏈球菌(S. pneumonia)、釀膿葡萄球菌(S. pyrogenes)、金黃色葡萄球菌和藤黃微球菌(M. luteus)的MIC均為64μg/mL(Jiang et al., 1997)。Streptomyces sp. B 8251代謝產(chǎn)生生物堿170, 具有微弱的抑制大腸桿菌(E. coli)和枯草芽孢桿菌(B. subtilis)的活性(Pusecker et al., 1997)。Anthranilamide (171)產(chǎn)自Streptomyces sp. B7747, 濃度為100μg/disk,對(duì)淡水小球藻(C. sorokiniana)的抑制圈直徑為11mm、對(duì)普通小球藻(C. vulgaris)的抑制圈直徑為 13mm、對(duì)柵藻(S. subspicatus)的抑制圈直徑為 12mm(Biabani et al., 1998)。Streptomyces sp. BD-18T(41)代謝產(chǎn)生多環(huán)苯醌類化合物 halawanones A-D(172～175)(Ford et al., 1998)。兩個(gè)弱的抗菌活性的芳香族胺類化合物 lornemides A(176)和 B(177)產(chǎn)自Streptomyces sp. MSTMA190, 176對(duì)枯草桿菌(B.subtilitis)的 LD99為 50μg/mL(Capon et al., 2000)?；衔?78～181來自Streptomyces sp. B5632和B3497(Mukku et al., 2000)?；衔?82和183分別來自Streptomyces sp. SS99BA-2 (Hernandez et al., 2000)和 Streptomyces sp. 1010(Ivanova et al., 2001), 化合物183對(duì)藤黃微球菌(M. luteus)和枯草芽孢桿菌(B. subtilis)的MIC分別為15μg/mL和50μg/mL, 而對(duì)白色念珠菌(C. albicans)和大腸桿菌(E. coli)沒有抑制活性。Streptomyces sp. M02750代謝產(chǎn)生化合物 184～189, 無抗白色念珠菌(C. albicans)活性(Cho et al., 2001)。大環(huán)內(nèi)酯chalcomycin B (190)產(chǎn)自Streptomyces sp. B7064, 其在濃度為10μg/9mm disk時(shí), 對(duì)金黃色葡萄球菌、大腸桿菌(E. coli)、枯草桿菌(B. subtilis)的抑菌圈直徑分別為23mm、28mm和21mm (Asolkar et al., 2002)?；衔?parimycin(191)來自Streptomyces sp. B8652, 其對(duì)GXF251L、H460、LXFA629L、LXFL529L、MCF-7、MAXF401NL、MEXF462NL和 MEXF 514L細(xì)胞的 IC70為0.9～6.7μg/mL(Maskey et al., 2002)?；衔飃utingimycin(192)也來源于該鏈霉菌(Maskey et al., 2004)。鏈霉菌Streptomyces sp. BD21-2代謝產(chǎn)生bonactin (193), 在測(cè)試濃度為1mg/mL時(shí),對(duì)金黃色葡萄球菌、芽孢桿菌(B. megaterium)和釀酒酵母菌(S. cerevisiae)的抑菌圈直徑分別為7mm、8mm和7.5mm (Schumacher et al., 2003)。Komodoquinone A (194)產(chǎn)自Streptomyces sp. KS3, 在1μg/mL時(shí), 即可誘導(dǎo)神經(jīng)母細(xì)胞瘤細(xì)胞株 Neuro 2A 的形態(tài)變化(Itoh et al., 2003)。內(nèi)酯類化合物195～196和大環(huán)內(nèi)酰胺類化合物197分別產(chǎn)自Streptomyces sp. B6007 (Stritzke et al., 2004) 和S. aureoverticillatus NPS001583(Mitchell et al., 2004), 對(duì)HT-29、B16-F10和人外周白血病細(xì)胞的EC50分別為3.6μmol/L、2.2μmol/L和2.3μmol/L。

Lajollamycin (198)產(chǎn)自鏈霉菌S. nodosus NPS007994, 對(duì)耐青霉素肺炎雙球菌(S. pneumonia)和耐甲氧西林葡萄球菌(S. aureus)的MIC分別為1.5μg/mL和5μg/mL, 對(duì)小鼠黑色素瘤細(xì)胞系B16-F10的EC50為9.6μmol/L (Manam et al., 2005)。氯代手霉素衍生物chinikomycins A (199)和B (200)來自Streptomyces sp. M045, 化合物 199對(duì)乳腺癌細(xì)胞 MAXF 401NL、黑色素瘤細(xì)胞MEXF 462NL和腎癌細(xì)胞 RXF 944L的 IC50分別為 2.41μg/mL、 4.15μg/mL 和 4.02μg/mL, 化合物 200對(duì)MAXF 401NL的 IC50為 3.04μg/ml(Li et al., 2005)。Streptomyces sp. NPS008187代謝產(chǎn)生glaciapyrroles A-C (201～203), 其中201對(duì)結(jié)直腸腺癌細(xì)胞HT-29和黑色素瘤細(xì)胞B16-F10的IC50均為180μmol/L(Macherla et al., 2005)。拒霉素衍生物204產(chǎn)自Streptomyces sp. B8005,抑制大腸桿菌(E. coli)、金黃色葡萄球菌和綠色產(chǎn)色鏈霉菌(S. viridochromogenes)的 MIC大于40μg/mL(Kock et al., 2005)。Actinofuranones A (205)和 B(206)產(chǎn)自 Streptomyces sp. CNQ766 (Cho et al., 2006a), 該菌株還代謝產(chǎn)生azamerone (207)(Cho et al., 2006b)。Daryamides A-C (208～210)、化合物211來自Streptomyces sp. CNQ-085, 化合物208對(duì)HCT-116細(xì)胞的IC50為3.15μg/mL, 化合物208～209對(duì)白色念珠菌的 MIC分別為 62.5μg/mL和 125μg/mL (Asolkar et al., 2006) (圖3)。

圖3 化合物116～211的結(jié)構(gòu)Fig.3 Structures of compounds 116～211

星孢菌素 N-carboxamidostaurosporine (212)、倍半萜類 213和生物堿類214來自鏈霉菌Streptomyces sp. QD518, 化合物214對(duì)膀胱、中樞神經(jīng)系統(tǒng)、結(jié)腸、胃、頭、頸、肺、乳房、胰腺、前列腺, 以及黑色素瘤等 37個(gè)人癌細(xì)胞的平均 IC50和 IC70值分別為0.016μg/mL和 0.17μg/mL, 化合物 214在40μg/disc時(shí)對(duì)金黃色葡萄球菌的抑菌圈直徑為11mm(Wu et al., 2006)。Streptomyces sp. CNQ-583代謝產(chǎn)生吡咯生物堿 bohemamine B (215)、bohemamine C (216)和 5-chlorobohemamine C(217)(Bugni et al., 2006)?；衔飖rauchimycin C (218)來自Streptomyces sp. B1751(Yao et al., 2006)。Streptokordin (219)產(chǎn)自Streptomyces sp. KORDI- 3238, 對(duì)細(xì)胞MDA-MB-231、HCT15、PC-3、NCI-H23、ACHN、LOX-IMVI、K-562的IC50值分別為7.5μg/mL、7.8μg/mL、3.2μg/mL、3.5μg/mL、4.7μg/mL、7.4μg/mL和 8.6μg/mL(Jeong et al., 2006)。Streptomyces sp. B8000代謝產(chǎn)生化合物 220和 221, 化合物 220在 40μg/disc時(shí), 對(duì)金黃色葡萄球菌和綠色鏈霉菌的抑菌圈直徑為分別為14mm和12mm(Poumale et al., 2006)。化合物octalactin C (222)來自Streptomyces sp. V5(陳光英等, 2007)。Streptomyces sp. M491代謝產(chǎn)生倍半萜化合物 223～225(Wu et al., 2007)和226～231(Ding et al., 2009), 化合物 226對(duì)多種腫瘤細(xì)胞的平均 IC50為6.7μg/mL。Streptomyces sp. CNH990代謝產(chǎn)生醌類化合物 marmycins A (232)和 marmycins B(233), 化合物232對(duì)人結(jié)腸癌細(xì)胞HCT-116的IC50為60.5nmol/L, 是其氯代同系物227的18倍(IC50為1.09 μmol/L), 232還具有G1期阻滯 活 性 (Martin et al., 2007)。 環(huán) 六 肽piperazimycins A-C (234～236)產(chǎn)自鏈霉菌Streptomyces sp. CNQ-593, 其對(duì)人結(jié)腸癌細(xì)胞HCT-116的平均GI50均為76ng/mL (Miller et al., 2007)。吡咯生物堿 marinopyrroles A (237)和 B (238)來自鏈霉菌 Streptomyces sp. CNQ-418, 其對(duì)耐甲氧西林金黃色葡萄球菌(MRSA)的 MIC90分別為 0.61μmol/L 和1.1μmol/L、對(duì) HCT-11細(xì)胞的 IC50分別為8.8μmol/L和9.0μmol/L(Hughes et al., 2008); 對(duì)該菌株優(yōu)化后又得到 marinopyrroles C-F (239～245), 對(duì)抑制人結(jié)腸癌 HCT-116細(xì)胞的IC50為1～5μg/mL, 化合物239抑制MRSA的MIC 小于 1μg/mL(Hughes et al., 2010)。Streptomyces sp. MS239代謝產(chǎn)生吲哚類化合物 243和萜類化合物 244, 化合物 243對(duì)枯草桿菌 ATCC6633有弱的抑菌活性(Motohashi et al., 2008)?；衔飁ssramycin (245)來自于Streptomyces sp. Merv8102, 其對(duì)革蘭陽(yáng)性菌和革蘭陰性菌的 MIC 為1.0～8.0μg/ml。對(duì)大腸桿菌(ATCC 10536)、銅綠假單胞菌(ATCC 10145)、枯草桿菌(ATCC 6051)、金黃色葡萄球菌(ATCC 6538)和藤黃微球菌(ATCC 9341)的 MIC分別為 8μg/mL、3.5μg/mL、1μg/mL、1μg/mL和1.5μg/mL (El-Gendy et al., 2008)。

Streptomyces sp H668代謝產(chǎn)生聚醚類化合物246, 有抗瘧疾活性, IC50為100～200ng/mL (Na et al., 2008)。有機(jī)酸 247和 248來自Streptomyces sp. Act8015 (Shaaban et al., 2008)。聚酮phaechromycins F-H (249～251)產(chǎn)自Streptomyces sp. DSS-18(Li et al., 2008)。Streptomyces sp. CNQ-617代謝產(chǎn)生marineosins A和 B(252～253), 其對(duì)人結(jié)腸癌細(xì)胞 HCT-116的 IC50分別為 0.5μmol/L 和 46μmol/L (Boonlarppradab et al., 2008); 對(duì)marineosins的生物合成研究, 又從該鏈霉菌的代謝產(chǎn)物中獲得了化合物254～257, 其中256對(duì)HepG2細(xì)胞的IC50為4.17μmol/L; 化合物256對(duì)氯喹敏感(CQS)、氯喹拮抗, 以及采用氯喹處理過的菌株P(guān). falciparum的IC50分別為2.3nmol/L、12nmol/L和1.5nmol/L (Salem et al., 2014)。三環(huán)聚丙酸酯類indoxamycins A-F (258～263)產(chǎn)自 Streptomyces sp. NPS-643, 化合物 258和 263對(duì)人結(jié)腸癌細(xì)胞 HT-29的 IC50為0.3～3μmol/L(Sato et al., 2009)。氯代生物堿ammosamides A (264)和B (265)產(chǎn)自鏈霉菌Streptomyces sp. CNR-698, 264暴露在空氣中可逐漸轉(zhuǎn)化為265, 其對(duì)人結(jié)腸癌HCT-116細(xì)胞的IC50均為320nmol/L, 作用靶點(diǎn)為肌球蛋白(Hughes et al., 2009)?；衔飐plenocins A-J (266～275)產(chǎn)自 Streptomyces sp. CNQ431, 抑制脾臟細(xì)胞因子的 IC50為 2～50nmol/L, 且對(duì)哺乳動(dòng)物細(xì)胞的細(xì)胞毒性較小, 具有治療哮喘的潛力(Strangman et al., 2009)。Streptomyces sp. NTK 227代謝產(chǎn)生albidopyrone A (276),具有蛋白酪氨酸磷酸酶 B(PTP1B)抑制活性, IC50為128μg/ml(Hohmann et al., 2009)。細(xì)胞毒活性的 mansouramycins A-D (277～280)和tartrolon D (281)分別產(chǎn)自 Streptomyces sp. Mei37(Hawas et al., 2009)和Streptomyces sp. MDG-04-17-069(Pérez et al., 2009), 化合物281對(duì)A549、HT29和MDA-MB-231的GI50分別為0.16μmol/L、0.31μmol/L和0.79μmol/L。二酮哌嗪naseseazines A (282)和B (283)產(chǎn)自Streptomyces sp. CMB-MQ030 (Raju et al., 2009)。Lorneic acids A (284)和B (285)產(chǎn)自Streptomyces sp. NPS554, 其抑制人血小板磷酸二酯酶5(PDE5)的IC50分別為12.6μmol/L和87.1μmol/L(Iwata et al., 2009); 多環(huán)聚酮類化合物akaeolide (286)也產(chǎn)自該菌, 其對(duì)大鼠成纖維細(xì)胞3Y1的IC50為8.5μmol/L(Igarashi et al., 2013)。Tirandamycins C (287)和D (288)產(chǎn)自Streptomyces sp. 307-9, 抑制耐萬(wàn)古霉素腸球菌(VRE)的 MIC分別為 110μmol/L和大于9μmol/L(Carlson et al., 2009)?；衔?89來自S. xiamenensis 318, 具有治療肺纖維化的潛力(Xu et al., 2012)。腫大鏈霉菌(S. tumescens) YM23-260產(chǎn)生環(huán)肽類化合物290和291, 化合物290在濃度為100μmol/L時(shí), 具有抑制阿爾茲海默病活性(Motohashi et al., 2010b)。環(huán)肽類化合物 292 產(chǎn)自 Streptomyces sp. MWW064, 具有抑制鼠腫瘤細(xì)胞 26-L5的轉(zhuǎn)移作用(Igarashi et al., 2010)。Streptomyces sp. CMB-M0406產(chǎn)生heronamides A-C (293～295)(Raju et al., 2010a)和 8-deoxyheronamide C (296)(Sugiyama et al., 2014), 296對(duì)裂殖酵母細(xì)胞的MIC可達(dá)5.8μmol/L?；衔?97～299為Streptomyces sp. CMB-M0423的代謝產(chǎn)物,對(duì)革蘭陽(yáng)性菌的IC50為0.6～6.5μmol/L(Raju et al., 2010b)(圖4)。 MDA-MB-231、HT-29和A549的GI50為0.24～

圖4 化合物212～298的結(jié)構(gòu)Fig.4 Structures of compounds 212～298

化合物 300～304產(chǎn)自 Streptomycetaceae CNQ-509, 化合物300、302和303對(duì)HCT-116細(xì)胞的 IC50分別為 31.1μmol/L、31.0μmol/L和5.7μmol/L(Kwon et al., 2010); Streptomyces sp. B6219代謝產(chǎn)生化合物305(Abdalla et al., 2010)。吡喃酮類化合物306～309產(chǎn)自S. albus POR-04-15-053, 化合物 306和 309對(duì)0.69μmol/L(Schleissner et al., 2011)?？姑顾豠ntimycins A19和A20(310～311)產(chǎn)自S. antibioticus H74-18, 其抑制白色念珠菌(C. albicans)的MIC為5～10μg/mL(Xu et al., 2011)。Streptomyces. sp CNQ-027代謝產(chǎn)生 actinoramides A-C (312～314)(Nam et al., 2011)和 actinoranone (315)(Nam et al., 2013), 化合物 315 對(duì)HCT-116細(xì)胞的LD50為2.0μg/mL。Streptomyces sp. RJA2928代謝產(chǎn)生 pandanamide B (316) (Williams et al., 2011)、nahuoic acid A (317) (Williams et al., 2013)和 nahuoic acids D-E (318～319)(Williams et al., 2016), 化合物316抑制 T淋巴細(xì)胞細(xì)胞的 IC50為 20μg/mL、化合物317和319對(duì)組蛋白甲基化酶的IC50分別6.5μmol/L和13μmol/L?？s酚酸肽fijimycins A-C (320～322)來自Streptomyces sp. CNS-575,其對(duì) MRSA (ATCC33591)、Sanger 252和UAMS1182的MIC100為4～16μg/mL(Sun et al., 2011)。Streptomyces sp. 211726代謝產(chǎn)生化合物323～324(Yuan et al., 2011)和325～331(Yuanet al., 2013), 對(duì)白色念珠菌(C. albicans)和人結(jié)腸癌細(xì)胞HCT-116有抑制活性?；衔?32產(chǎn)自 Streptomyces sp. 061316 (Chen et al, 2011)。安沙霉素類化合物ansalactam A (333)來自 Streptomyces sp. CNH-189(Wilson et al., 2011); 該菌還代謝產(chǎn)生混源萜 334～337 (Kaysser et al., 2012)和ansalactams B-D (338～ 340)(Le et al., 2016), 化合物338～340對(duì)MRSA的 MIC 分別為 31.2μg/mL、31.2μg/mL 和62.5μg/mL?；衔?benzoxacystol (341)來自Streptomyces sp. NTK 935, 抑制糖原合成酶激酶GSK-3β的IC50為1.35μmol/L, 對(duì)小鼠成纖維細(xì)胞NIH- 3T3有弱抑制活性(Nachtigall et al., 2011)。Streptomyces sp. B8112代謝產(chǎn)生glucopiericidin C (342), 有抗米黑毛霉菌活性和細(xì)胞毒活性 (Shaaban et al., 2011)。Streptomyces sp. MST- MA568代謝產(chǎn)生螺環(huán)縮酮 reveromycin E (343)(Fremlin et al., 2011)。吡喃酮A-C (344～346)產(chǎn)自Streptomyces sp. CNQ-301 (Fukuda et al, 2011)。Streptomyces sp. WuXin代謝產(chǎn)生化合物 347和 348, 對(duì)HL-60有細(xì)胞毒活性(Li et al., 2011); 化合物usabamycin A-C (349～351)產(chǎn)自Streptomyces sp. NPS853, 對(duì)人宮頸癌HeLa細(xì)胞有弱細(xì)胞毒活性并可選擇性抑制對(duì) 5-羥色胺的攝取(Sato et al., 2011)。Streptomyces sp. W007代謝產(chǎn)生化合物352, 對(duì)A549細(xì)胞有細(xì)胞毒活性(Zhang et al., 2011)(圖5)。

圖5 化合物299～352的結(jié)構(gòu)Fig.5 Structures of compounds 299～352

化合物 353 產(chǎn)自桿菌狀鏈霉菌 S. bacillaris SNB-019(Hu and MacMillan, 2012)。對(duì)弗氏鏈霉菌S. fradiae 007進(jìn)行紫外照射和亞硝基胍誘變, 得到突變株 S. fradiae 007M135, 該突變株代謝產(chǎn)生吲哚咔唑生物堿 354～356, 其對(duì) HL-60、K562、A549、BEL-7402細(xì)胞均有抑制活性, 對(duì)蛋白激酶 C (PKC-α)的IC50值為0.001～4.6μmol/L(Fu et al., 2012a)。糖苷類化合物 357～361來自 S. lusitanus SCSIO LR32, 357～360對(duì)多個(gè)腫瘤細(xì)胞的 IC50值為 1.1～31μmol/L (Huang et al., 2012)。Streptomyces sp. CMB-M0392代謝產(chǎn)生化合物 362, 對(duì)枯草桿菌 ATCC6052和ATCC6633的IC50分別為8μmol/L和14μmol/L (Raju et al., 2012)。化合物 363和 364產(chǎn)自Streptomyces sp. CNQ343, 化合物363對(duì)白色念珠菌有較強(qiáng)的抑制活性(Kim et al., 2012)。Streptomyces sp. SCSIO 03032代謝產(chǎn)生吲哚生物堿365～368(Zhang et al., 2012)、indimicins A-E (369～373)、lynamicin F (374)和lynamicin G (375)(Chen et al., 2014), 以及piericidin A1 (376)(Zhang et al., 2014a)、heronamides D-F (377～379)(Zhang et al., 2014b), 化合物366～ 368對(duì)多種腫瘤細(xì)胞的 IC50為 4～15μmol/L、370對(duì)MCF-7的IC50為10.0μmol/L。吩嗪類化合物380為Streptomyces sp. LB173的代謝產(chǎn)物, 有微弱的抗菌活性, 是一種乙酰膽堿酯酶抑制劑(Ohlendorf et al., 2012)?；衔?81產(chǎn)自Streptomyces sp. M268(Xie et al., 2012);化合物382～385產(chǎn)自Streptomyces sp. SCSIO 02999(Zhang et al., 2012), 4個(gè)化合物對(duì)致病菌的MIC分別為E.coli ATCC 25922(8μg/mL、8μg/mL、16μg/mL 和 4μg/mL)、S.aureus ATCC29 213(8μg/mL、16μg/mL、16μg/mL、8μg/mL)、B.subtilis SCSIO BS01(64μg/mL、128μg/mL、大于 128μg/mL、64μg/mL)和 B. thuringiensis SCSIO BT01(64μg/mL、64μg/mL、大于128μg/mL、大于128μg/mL)?；衔?86產(chǎn)自Streptomyces sp. CP13-10, 對(duì)酵母Sir2p基因的MIC為2.5mmol/L、對(duì)人類SIRT1和 SIRT2基因的 IC50分別為 3.7 mmol/L和4.5mmol/L(Amagata et al., 2012)。

S. variabilis SNA-020代謝產(chǎn)生生物堿387, 387對(duì)胰腺細(xì)胞 MIA PaCa-2的 IC50為3.2μmol/L(Pan et al., 2012)?；衔?88產(chǎn)自Streptomyces sp. TP-A0879, 對(duì)小鼠結(jié)腸癌細(xì)胞26-L5的IC50為0.25μmol/L(Igarashi et al., 2012)。吲哚咔唑生物堿389和390產(chǎn)自Streptomyces sp. FMA, 化合物 390 對(duì)HL-60、A549和 Hela細(xì)胞的 IC50值分別為1.4μmol/L、5.0μmol/L和34.5μmol/L(Fu et al., 2012b)。Streptomyces sp. CNT-179代謝產(chǎn)生cyanosporasides D-F (391～393)(Lane et al., 2013); S. antibioticus PTZ0016 代謝產(chǎn)生394～396, 化合物 394～396對(duì)金黃色葡萄球菌ATCC6538的 MIC 分別為 6.0mg/mL、6.0mg/mL 和 8.0mg/mL(Lian and Zhang, 2013)。生物堿nitrosporeusines A (397)和B (398)產(chǎn)自S. nitrosporeus CQT1424, 具有抑制甲型H1N1流感病毒活性(Yang et al., 2013a)。S. niveus SCSIO 3406代謝產(chǎn)生倍半萜marfuraquinocins A-D (399～402)、phenaziterpenes A (403)和B (404), 化合物399和401對(duì)肺癌細(xì)胞 NCI-H460的 IC50值分別為 3.7μmol/L和4.4μmol/L, 化合物399、401和402對(duì)金黃色葡萄球菌 ATCC292138的 MIC值均為8μg/mL; 化合物401和402對(duì)耐甲氧西表皮葡萄球菌shhs-E1的MIC值為8μg/mL(Song et al., 2013)。Streptomyces sp. CNH-287代謝產(chǎn)生chlorizidine A (405), 其對(duì)HCT-116細(xì)胞的IC50為3.2～4.9μmol/L (Alvarez-Mico et al., 2013)。脫氫二酮哌嗪406～410產(chǎn)自Streptomyces sp. FXJ7.328, 化合物407抑制H1N1病毒的IC50為 41.5μmol/L(Wang et al., 2013)。Streptomyces sp. MS100061 代 謝 產(chǎn) 生lobophorin G1 (411), 其對(duì)枯草芽胞桿菌和結(jié)核分支桿菌H37Rv的MIC分別為3.1μg/mL和32μg/mL(Chen et al., 2013)(圖6)。

圖6 化合物353～410的結(jié)構(gòu)Fig.6 Structures of compounds 353～410

Streptomyces sp. SNJ013代謝產(chǎn)生化合物sungsanpin (412)(Um et al., 2013a)。Streptomyces sp. CNQ-329 代謝 產(chǎn) 生 napyradiomycins A-E(413～417), 化合物 413、416和 417對(duì)HCT-116細(xì)胞的IC50為4.2μg/mL、16.1μg/mL和4.8μg/mL, 化合物413和414對(duì)MRSA的MIC分別為26μg/mL和64μg/mL(Cheng et al., 2013)。 Streptomyces sp. CNH-070 產(chǎn) 生napyradiomycin F (418), 其對(duì)HCT-116細(xì)胞的IC50為9.42μg/mL(Cheng et al., 2013)。Streptomyces sp. SCSIO 10428代謝產(chǎn)生化合物419～421, 化合物419對(duì)金黃色葡萄球菌ATCC29213、枯草芽胞桿菌SCSIO BS01和蘇云金桿菌SCSIO BT01的 MIC分別為 4μg/mL、4μg/mL和 8μg/mL, 化合物 420對(duì)金黃色葡萄球菌ATCC29213、枯草芽胞桿菌SCSIO BS01和蘇云金桿菌 SCSIO BT01的 MIC分別為0.5μg/mL、1μg/mL和1μg/mL, 化合物421對(duì)枯草芽胞桿菌 SCSIO BS01和蘇云金桿菌SCSIO BT01的 MIC分別為 8μg/mL和16μg/mL (Wu et al., 2013a)?；衔颽nthracimycin (422) 來自Streptomyces sp. CNH365, 對(duì)炭疽芽胞桿菌 UM23C1-1、金黃色葡萄球菌ATCC 13709、糞腸球菌 ATCC 29212、肺炎鏈球菌ATCC 51916、流感嗜血桿菌ATCC 31517KO的MIC分別為0.03125μg/mL、0.0625μg/mL、0.125μg/mL、0.25μg/mL和4μg/mL(Jang et al., 2013)。環(huán)肽surugamides A-E (423～427)來自

Streptomyces sp. JAMM992, 對(duì)牛組織蛋白酶B 的 IC50分別為 21μmol/L、27μmol/L、36μmol/L、18μmol/L和16μmol/L(Takada et al., 2013)。Streptomyces sp. SCSIO 03219代謝產(chǎn)生萜類化合物 03219A (428) (Zhang et al., 2013)。Streptomyces sp. Eg25 代謝產(chǎn)生maroxazinone (429), 對(duì) MCF7、HEPG2和HCT116細(xì)胞的 IC50分別為 4.32μg/mL、2.90μg/mL和8.51μg/mL(Abdelfattah, 2013)。Streptomyces sp. CNT-372代謝產(chǎn)生farnesides A (430) 和B (431), 430對(duì)惡性瘧原蟲的IC50為69.3μmol/L(Zafrir et al., 2013)。Streptomyces sp. 7-145代謝產(chǎn)生化合物432和433, 對(duì)耐甲氧西林金黃色葡萄球菌和耐萬(wàn)古霉素腸球菌有很好的抗菌活性(Wu et al., 2013b)。環(huán)肽ohmyungsamycin A(434)和 ohmyungsamycin B(435)產(chǎn)自鏈霉菌 Streptomyces sp. SNJ042,化合物434對(duì)枯草芽胞桿菌ATCC6633、藤黃微球菌NBRC12708和變形桿菌NBRC3851的MIC 分別為 4.28μmol/L、1.07μmol/L 和2.14μmol/L, 化合物 435 對(duì)藤黃微球菌NBRC12708的MIC為8.5μmol/L, 化合物434對(duì)HCT116、A549、SNU-638、MDAMB-231和SKHEP-1細(xì)胞的IC50分別為0.359μmol/L、0.551μmol/L、0.532μmol/L、0.688μmol/L和0.816μmol/L(Um et al., 2013b)。Separacenes A-D(436～439) 產(chǎn)自Streptomyces sp. SNJ210,化合物436對(duì)白色念珠菌異檸檬酸裂解酶、人癌細(xì)胞HCT-116和A549有弱活性(Bae et al., 2013)。Streptomyces sp. 12A35代謝產(chǎn)生lobophorins H (440)和I (441), 化合物440對(duì)金黃色葡萄球菌ATCC29213和枯草芽胞桿菌CMCC63501的 MIC分別為 50μg/mL和1.57μg/mL(Pan et al., 2013)。Strepsesquitriol (442)來自 Streptomyces sp. SCSIO 10355, 具有抑制 TNF-α的活性(Yang et al., 2013b)。Mollemycin A (443) 產(chǎn)自 Streptomyces sp. CMBM0244, 對(duì)金黃色葡萄球菌 ATCC 25293和 ATCC 9144、表皮葡萄球菌ATCC12228、枯草芽胞桿菌 ATCC 6051和ATCC 6633、大腸桿菌ATCC 25922、綠膿桿菌 ATCC 27853和牛結(jié)核桿菌的IC50值分別為50nmol/L、10nmol/L、50nmol/L、10nmol/L、10nmol/L、10nmol/L、50nmol/L和3200nmol/L;對(duì)藥敏型和多藥耐藥的惡性瘧原蟲的 IC50分別為 9nmol/L和 7nmol/L, 活性遠(yuǎn)大于氯喹,與青蒿素相當(dāng)(Raju et al., 2014)。S. drozdowiczii SCSIO 10141代謝產(chǎn)生 marformycins A-F (444～449), 化合物 444～448對(duì)藤黃微球菌的MIC 分 別 為 0.25mg/mL、 4.0mg/mL、0.25mg/mL、0.063mg/mL和4.0mg/mL (Zhou et al., 2014)。S. nitrosporeus YBH10-5代謝產(chǎn)生nitrosporeunols A-G (450～456)(Liu et al., 2014)。S. scopuliridis SCSIO ZJ46代謝產(chǎn)生化合物 457～459, 457對(duì)金黃色葡萄球菌ATCC 29213、肺炎雙球菌NCTC 7466、耐甲氧西林表皮葡萄球菌的 MIC 值分別為16.0μg/mL、12.5μg/mL和32.0μg/mL (Song et al., 2014)(圖7)。

圖7 化合物411～459的結(jié)構(gòu)Fig.7 Structures of compounds 411～459

Streptomyces sp. LZ35DgdmAI代謝產(chǎn)生echosides A-E (460～464), 化合物460有很明顯的拓?fù)洚悩?gòu)酶Ⅰ活性, 化合物462有拓?fù)洚悩?gòu)酶 IIa活性(Deng et al., 2014)。化合物465～468產(chǎn)自Streptomycetaceae CNQ525, 可以誘導(dǎo) HCT-116細(xì)胞凋亡(Farnaes et al., 2014)。Streptomyces sp. ACT232代謝產(chǎn)生ahpatinin Ac (469)和ahpatinin Pr (470), 對(duì)胃蛋白酶的IC50為11～50nmol/L (Sun et al., 2014a)。Carpatamides A-C(471～473)來自Streptomyces sp. SNE-011, 化合物471和473對(duì)NSCLC、HCC366、A549和 HCC44細(xì)胞的 IC50為2.2～8.4 μmol/L (Fu et al., 2014)?；衔颽nmindenols A (474) 和 B (475) 產(chǎn)自Streptomyces sp. CMDD10D111, 抑制NO產(chǎn)生的 IC50值為 23μmol/L和 19μmol/L (Lee et al., 2014)。Arcticoside (476)和 C-1027 chromophore-V (477)產(chǎn)自 Streptomyces sp. ART5, 化合物476和477對(duì)白色念珠菌異檸檬酸(裂合)酶的 IC50分別為 30.4μmol/L和37.9μmol/L; 化合物 477對(duì)癌細(xì)胞 MDAMB231和HCT-116的IC50分別為0.9μmol/L和2.7μmol/L(Moon et al., 2014)。Lajollamycins B?D (478～480)產(chǎn)自鏈霉菌 Streptomyces sp. SMC72, 對(duì)白色念珠菌異檸檬酸裂解酶的IC50分別為40μmol/L、50μmol/L和120μmol/L (Ko et al., 2014)。Streptomyces sp. SNM55代謝產(chǎn)生mohangamides A (481)和B (482)(Bae et al., 2015b)、hormaomycins B (483) 和C (484) (Bae et al., 2015a), 化合物481和482對(duì)白色念珠菌 ICL 的 IC50分別為 4.4μmol/L 和20.5μmol/L, 化合物 483/484對(duì)金黃色葡萄球菌ATCC 25923、枯草芽胞桿菌 ATCC 6633、藤黃微球菌 NBRC 12708、化膿性鏈球菌ATCC 19615、腸道沙門菌ATCC 14028和P.hauseri NBRC 3851的MIC分別為7/7μmol/L、14/56μmol/L、0.4/0.23μmol/L、14/8μmol/L、29/114μmol/L和29/14μmol/L。Streptomyces sp. IFM 11440代謝產(chǎn)生nubosins A-C (485～487),化合物486具有Ngn2基因啟動(dòng)子的活性、促進(jìn)神經(jīng)干細(xì)胞分化基因有關(guān)的mRNA的表達(dá)(Arai et al., 2015)。Streptomyces sp. SCSIO 11594代謝產(chǎn)生marangucyclines A (488)和B (489), 化合物489對(duì)A549、CNE2、MCF-7、HepG2和HL7702細(xì)胞的IC50分別為0.45μmol/L、0.56μmol/L、0.24μmol/L、0.43μmol/L和3.67μmol/L (Song et al., 2015)。Suncheonosides A-D (490～ 493)來自 Streptomyces sp. SSC21, 化合物490、491和493能促進(jìn)脂聯(lián)素的產(chǎn)生, 具有降糖的潛力(Shin et al., 2015)。二酮哌嗪494產(chǎn)自 Streptomyces sp. SCSIO 04496(Luo et al., 2016)。Rocheicoside A (495)和rocheicoside 496產(chǎn)自S. rochei 06CM016, 化合物495對(duì)大腸桿菌O157: H7 RSKK 234、耐甲氧西林金黃色葡萄球菌 DSM 11729 和人白色念珠菌 DSM 5817的 MIC分別為 16μg/mL、8μg/mL和4μg/mL; 化合物496對(duì)這3株致病菌的MIC分別為16μg/mL、16μg/mL和8μg/mL (Aksoy et al., 2016)。Streptomyces sp. IFM11490代謝產(chǎn)生elmonin (497)、elmenols A (498)和elmenols B (499), 化合物497和499對(duì)AGS細(xì)胞有弱細(xì)胞毒活性(Yixizhuoma et al., 2015)。Streptomyces sp. SNB-048代謝產(chǎn)生spinoxazines A (500)和spinoxazines B (501)、bohemamine D-I (502～ 507)(Fu et al., 2016)。Streptomyces sp. CHQ-64代謝產(chǎn)生 drimentine I (508), 對(duì) Hela的 IC50為16.7μmol/L(Che et al., 2016)。Streptomyces sp. 10A085代謝產(chǎn)生anithiactins A-C (509～ 511), 其對(duì)乙酰膽堿酯酶的 IC50分別為63μmol/L、53μmol/L和68μmol/L(Kim et al., 2014)(圖8)。

多環(huán)蒽醌512和513來自Streptomyces sp. 182SMLY, 對(duì)C6、U251、U87-MG和SHG-44c 4種膠質(zhì)瘤細(xì)胞的IC50為0.5～7.3μmol/L; 化合物512對(duì)S. aureus的MIC為20.0μmol/L(Liang et al., 2016b); 該菌株還代謝產(chǎn)生吩嗪類化合物 514～516(Liang et al., 2016a)。Mohangic acids A-E (517～521)來自 Streptomyces sp. SNM31, 化合物 521對(duì)醌還原酶具有良好的活性, 當(dāng)濃度為 20μmol/L時(shí), 活性是陽(yáng)性藥β-萘黃酮的2.1倍(Bae et al., 2016)。Actinoquinolines A (522)和 B (523)產(chǎn)自 Streptomyces sp. CNP975, 對(duì)環(huán)氧化酶 COX-1的 IC50分別為7.6μmol/L和2.13μmol/L, 對(duì)環(huán)氧化酶COX-2的 IC50分別為 24.9μmol/L 和 1.42μmol/L (Hassan et al., 2016)。麥角脂醇類化合物ananstreps A-C (524～526)來自 S. anandii H41-59, 其中化合物 526對(duì) SF-268、MCF-7和 NCI-H460的 IC50分別為 13.0μg/mL、18.1μg/mL和23.5μg/mL (Zhang et al., 2016)。

3.2 海水來源的鏈霉菌天然產(chǎn)物

海水來源的鏈霉菌(下同)Streptomyces sp. Z00045代謝產(chǎn)生cycloheximide acid A (527) (Xu et al., 2013)。Streptomyces sp. F001代謝產(chǎn)生diazaquinomycins E-G (528～530), 528對(duì)卵巢癌 OVCAR5細(xì)胞的 IC50為 9.0μmol/L (Mullowney et al., 2014)。Streptomyces sp. TPU1236A 代謝產(chǎn)生 streptcytosines A-E (531～535), 531對(duì)恥垢分枝桿菌的 MIC為32μg/mL (Bu et al., 2014)。一株gntR基因突變的鏈霉菌代謝產(chǎn)生化合物536～538 (Liu et al., 2015)。

4 未知來源的海洋鏈霉菌天然產(chǎn)物

來源未知的鏈霉菌(下同)Streptomyces sp. GWS-BW-H5產(chǎn)生內(nèi)酯類化合物 539～544 (Dickschat et al., 2005)。降倍半萜 545來自Streptomyces sp. 0616208, 對(duì)肝瘤細(xì)胞 SMMC-7721有細(xì)胞毒活性(Xie et al., 2006)。吩嗪類化合物 546和 547產(chǎn)自 Streptomyces sp. CNS284, 其對(duì)TNF-α介導(dǎo)的NFκB有抑制作用, IC50分別為4.1μmol/L和24.2μmol/L; 抑制LPS介導(dǎo)的NO的IC50分別為48.6μmol/L和15.1μmol/L; 對(duì)細(xì)胞生長(zhǎng)和調(diào)節(jié)因子——前列腺素 E2(PGE2)有抑制作用, IC50分別是7.5μmol/L 和 0.89μmol/L(Kondratyuk et al., 2012)(圖9)。

圖8 化合物460～502的結(jié)構(gòu)Fig.8 Structures of compounds 460～502

綜上所述, 從 1976年報(bào)道的首例海洋鏈霉菌來源的aplasmomycins A-C(Okami et al., 1976)到2016年6月的40年時(shí)間里, 一共報(bào)道了547個(gè)海洋鏈霉菌新天然產(chǎn)物(表1)。其結(jié)構(gòu)類型呈現(xiàn)多樣性, 涉及含氮化合物, 如生物堿、聚酮、萜類、甾體、糖苷、聚醚類及其鹵代物等, 且67.3%的化合物表現(xiàn)出腫瘤細(xì)胞毒、抗菌、抗瘧、抗寄生蟲, 以及糖苷酶抑制等生物活性(表 1), 是發(fā)現(xiàn)海洋活性化合物的重要資源。

(1) 從海洋鏈霉菌NPs的數(shù)量看, 新化合物的數(shù)量呈現(xiàn)年遞增的趨勢(shì)。從2006年開始,新化合物遞增的趨勢(shì)越來越顯著, 2014年最多, 報(bào)道了82個(gè)(圖10)。

(2) 從海洋鏈霉菌的樣品來源看, 產(chǎn)生新化合物最多的海洋鏈霉菌的來源依次是海泥(377個(gè))、海綿(64個(gè))和其他海洋動(dòng)物(34個(gè)), 分別占68.9%、11.7%和6.2%(圖11)。

(3) 從化合物的結(jié)構(gòu)類型看, 化合物最多的類型依次是含氮(336個(gè))和聚酮(196個(gè)), 分別占海洋鏈霉菌 NPs總數(shù)的 61.4%和 35.8% (圖12)。

(4) 約 67.3%的海洋鏈霉菌 NPs(368個(gè))表現(xiàn)出腫瘤細(xì)胞毒、抗菌、抗瘧和抗寄生蟲等生物活性, 而腫瘤細(xì)胞毒活性(141個(gè))和抑菌活性(117個(gè))是主要的活性類型, 分別占活性化合物總數(shù)的38.3%和31.8%(圖13)。

(5) 歐美、中國(guó)和其他亞洲國(guó)家是海洋鏈霉菌NPs的主要發(fā)現(xiàn)者, 其發(fā)表化合物的數(shù)量分別為 256個(gè)、163個(gè)和 112個(gè), 我國(guó)學(xué)者貢獻(xiàn)了29.8%的海洋鏈霉菌 NPs(圖14見文后彩圖); 歐美、中國(guó)和其他亞洲國(guó)家的學(xué)者分別發(fā)表了 93篇、63篇和52篇文章, 其他國(guó)家發(fā)表了9篇相關(guān)文章, 分別占42.9%、29.0%、24.0%和4.1%。

圖9 化合物503～547的結(jié)構(gòu)Fig.9 Structures of compounds 503～547

圖10 每年從海洋鏈霉菌的代謝產(chǎn)物中分離的天然產(chǎn)物的數(shù)量Fig.10 Annual number of marine-derived Streptomyces actinomycetes MNPs since 1976

圖11 海洋鏈霉菌天然產(chǎn)物的來源Fig.11 Origin categoriesof marine-derived Streptomyces actinomycetes MNPs

圖12 海洋鏈霉菌天然產(chǎn)物的結(jié)構(gòu)分類Fig.12 The main structure types of marine-derived Streptomyces actinomycetes MNPs

圖13 海洋鏈霉菌天然產(chǎn)物的活性分類Fig.13 Bioactive categories of marine-derived Streptomyces actinomycetes MNPs

圖14 海洋鏈霉菌天然產(chǎn)物的主要發(fā)現(xiàn)者國(guó)別Fig.14 Country categories of the main discoverers on Streptomyces MNPs

(6) 我國(guó)學(xué)者在 63篇學(xué)術(shù)文章中貢獻(xiàn)了163個(gè)海洋鏈霉菌NPs, 在天然產(chǎn)物化學(xué)類、有機(jī)化學(xué)類和海洋藥物類的主流雜志, 如 J Nat Prod、Org Lett、J Org Chem和Mar Drugs的學(xué)術(shù)文章分別有11篇、7篇、1篇和13篇,占其文章總數(shù)的17.5%、11.1%、1.6%和20.6% (圖15)。

圖15 中國(guó)學(xué)者發(fā)表論文的期刊分類Fig.15 Journal categories of Chinese scholars for publishing Streptomyces MNPs

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New Natural Products From the Marine-Derived Streptomyces Actinobacteria

WANG Cong, MEI Xian-Gui, ZHU Wei-Ming*
(Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China) *Corresponding author, E-mail: weimingzhu@ouc.edu.cn

Marine-derived Streptomyces were the chief source of the bioactive marine natural products (MNPs) from marine microbial origin owing to their unique physiological and metabolic functions. According to statistic results for MNPs from 2010 to 2013, marine-derived Streptomyces attributed to 60% MNPs sourced from marine-derived actinobacteria. This paper reviews the sources, structures and bioactivities of the 547 new MNPs of Streptomyces origin in 40 years from 1976 to June 2016. These MNPs have diverse structures including alkaloids, polyketides, sterols and terpenoids, and so on. Nitrogen compounds are the major structural types making up 61% MNPs from Streptomyces. And 67% MNPs sourced from Streptomyces showed bioactivities such as cytotoxicity, antimicrobial activity, antimalaric and insecticidal activity.

marine-derived actinobacteria; Streptomyces sp.; natural products; sources; chemical structures; bioactivities

R282.77

10.12036/hykxjk20160711002

* 資助項(xiàng)目: 國(guó)家自然科學(xué)基金項(xiàng)目(81561148012, U1501221, U1406402-1, 41376148)。王聰, 男, 博士研究生, E-mail: wangcong123206@163.com

① 通訊作者: 朱偉明, 男, 教授, 從事海洋微生物藥物化學(xué)和天然藥物的優(yōu)化等研究工作, E-mail: weimingzhu@ouc.edu.cn

2016-07-11, 收修改稿日期: 2016-08-02