具有抗癌活性的喜树碱类化合物的构效关系研究

目的 探寻喜树碱类似物的电子结构与抗癌活性的关系。方法 应用分子力学MM 法、量子化学从头算法和AMl法对18个喜树碱类似物进行几何优化，计算了化合物的电子结构，并应用逐步回归方法探寻化合物量子化学指数和抗癌活性的关系。结果 (1)喜树碱类似物的1og P与活性参数间呈抛物线关系；(2)分子的log P及20位碳原子电荷是影响化合物抗癌活性的重要因素；7位取代基的疏水参数1og P2对分子的log P影响很大；(3)得到较显著的QSAR方程：pIC50＝38．123 8．0907log P—0．81425(log P)^2—682．379QC20。结论 疏水性对喜树碱类似物的活性影响较大；D环及相连的羰基氧O23可能是与受体作用的活性中心；根据所得的QSAR及方程可以较准确地预测喜树碱类似物地活性。     

Structural studies on bioactive compounds. 4. A structure-antitumor activity study on analogues of N-methylformamide

A series of derivatives of N-methylformamide (NMF), an experimental antitumor agent, has been prepared, having the general formula R3C(X)NR1R2 where R1 = H, CH3, CD3, CH2CF3, CH2CH2Cl, cyclopropyl, C2H5, CH2OH, CH2OR, CH2N(CH3)2; R2 = H, CH3; R3 = H, CF3, CCl3, CH3, Ph, NHCH3, N(CH3)2; and X = O, S, NH. A further short series of "push-pull" olefins of the general formula R1R2C = CHNR3R4 has been synthesized where R1 = H, CH3 and R2 = H, NO2, CN, CHO, CH3 and R3 = H and R4 = H, CH3, morpholino. These compounds have been tested for activity against the M5076 ovarian sarcoma and the TLX5 lymphoma in mice. NMF was by far the most potent agent of both series with activity against both tumors. Some other compounds showed weak activity, but there is a rigorous structural requirement for activity and most analogues were inactive. Certain members of the series exist as equilibrium mixtures of rotamers about the amide or pro-amide bonds as shown by NMR.     

Synthesis and cytotoxic activity of polyamine analogues of camptothecin

A number of derivatives of camptothecin with a polyamine chain linked to position 7 of camptothecin via an amino, imino, or oxyiminomethyl group were synthesized and tested for their biological activity. All compounds showed marked growth inhibitory activity against the H460 human lung carcinoma cell line. In particular, the iminomethyl derivatives where the amino groups of the chain were protected with Boc groups exhibited a high potency, with IC50 values of approximately 10(-8) M. The pattern of DNA cleavage in vitro and the persistence of the cleavable ternary complex drug-DNA-topoisomerase I observed with polyamine conjugates containing free amino groups support a contribution of specific drug interaction with DNA as a determinant of activity. Modeling of compound 7c in the complex with topoisomerase 1 and DNA is consistent with this hypothesis. The lack of a specific correlation between stabilization of the cleavable complex and growth inhibition likely reflects multiple factors including the cellular pharmacokinetic behavior related to the variable lipophilicity of the conjugate, and the nature and linkage of the polyamine moiety.     

紫杉醇类衍生物的定量结构-抗癌活性关系研究进展

该文就目前以分子模拟为手段的紫杉醇类分子的定量结构-抗癌活性关系研究进行了综述。主要围绕该类分子结构的关键活性基团,即C13侧链、C14、C2、C10位基团及四元氧环对活性的贡献进行论述,总结了目前此类研究达成的共识及争议。此外,对结构之外的其他活性影响因素及活性分类研究也进行了汇总。     

六环喜树碱衍生物的合成与抗肿瘤活性研究

目的研究在喜树碱类化合物A环9,10位上增加一个六元环后，所得衍生物的生物活性的变化情况。方法分别以10-羟基喜树碱和7-乙基-10-羟基喜树碱(SN-38)为原料,通过三或四步反应得到一系列相应的A环上修饰的喜树碱衍生物,用MTT法评价了它们的细胞毒活性，用小鼠肝癌H₂₂评价它们体内的肿瘤抑制率。结果5个六环喜树碱衍生物为目标化合物，10个衍生物为新化合物。结论喜树碱A环的9,10位增加一个“1,4-氧嗪-2-酮”六元环后，其抗肿瘤活性要比喜树碱或10-羟基喜树碱的活性降低。     

Alternative administration of camptothecin analogues

In order to improve the therapeutic index of camptothecin (CPT) analogues, alternative administration of CPT analogues is being evaluated. Topotecan, irinotecan, rubitecan, lurtotecan and 9-aminocamptothecin have been administered orally with response rates equivalent to that seen after intravenous administration, where applicable. Oral availability and administration of some of the newer CPT analogues, including diflomotecan (BN80915) and grimatecan (ST1481), have also shown promising results. Aerosolisation of liposomal 9-nitrocamptothecin has been studied in patients with advanced malignancies involving the lung, demonstrating systemic antitumour activity. Intrathecal administration of topotecan has been studied in children with refractory neoplastic meningitis. It is well tolerated and associated with some antitumour activity. Intraperitoneal administration of topotecan as consolidation therapy in patients with ovarian cancer has shown promising results. Transdermal administration of rubitecan has been studied in mice. So far, no CPT has been approved for an alternative route of administration.     

Alternative administration of camptothecin analogues

In order to improve the therapeutic index of camptothecin (CPT) analogues, alternative administration of CPT analogues is being evaluated. Topotecan, irinotecan, rubitecan, lurtotecan and 9-aminocamptothecin have been administered orally with response rates equivalent to that seen after intravenous administration, where applicable. Oral availability and administration of some of the newer CPT analogues, including diflomotecan (BN80915) and grimatecan (ST1481), have also shown promising results. Aerosolisation of liposomal 9-nitrocamptothecin has been studied in patients with advanced malignancies involving the lung, demonstrating systemic antitumour activity. Intrathecal administration of topotecan has been studied in children with refractory neoplastic meningitis. It is well tolerated and associated with some antitumour activity. Intraperitoneal administration of topotecan as consolidation therapy in patients with ovarian cancer has shown promising results. Transdermal administration of rubitecan has been studied in mice. So far, no CPT has been approved for an alternative route of administration.     

Quantitative structure-activity relationships and carminative activity

Carminative activities of 34 alcohols, esters, ethers, phenols, and carbonyl compounds were determined using the guinea pig isolated ileum preparation and are expressed as the ability to produce a 50% inhibition (ID50) of a standard response to carbachol. Aqueous solubilities were measured at 37 degrees using either UV absorption or GLC. The ratios of solubility to ID50 were reasonably constant, suggesting nonspecific biological activity, similar to that previously observed with general anesthetics. Hansch analysis indicated that carminative activities were largely controlled by solubility, as indicated by octanol-water distribution coefficients. The principal remaining factor appeared to be the steric availability of the oxygen atom in the functional group of the compound.     

Plant antitumor agents. 23. Synthesis and antileukemic activity of camptothecin analogues

Eight optically active and nine racemic ring A modified analogues of 20(S)-camptothecin were prepared and evaluated for antitumor activity in the L-1210 leukemia system. The ring A mono- and disubstituted analogues displayed a wide variance in activity and potency. It was found that monosubstitution by NH2 or OH at positions 9, 10, or 11 yielded compounds with activity much higher than the parent compound, camptothecin, whereas substitution at position 12 greatly reduced activity. In general, disubstitution in ring A greatly reduced antileukemic activity. Replacement of ring A by heterocyclic rings (thiophene or pyridine) leads to analogues with only moderate activity.     

Absolute structure-cytotoxic activity relationships of steganacin congeners and analogues

The cytotoxic activities of optically pure and racemic steganacin congeners and analogues against KB cells in culture and the inhibitor activity of cilia regeneration in Tetrahymena were studied with regard to absolute and relative configurations. The stereochemical requirements of dibenzocyclooctadiene lignan lactones for activity were clarified.     

喜树碱及其衍生物的研究进展

喜树碱及其衍生物有较强的抗癌活性，作用靶点为拓扑异构酶I，构效关系显示喜树碱内酯的E环对其活性影响较大，并确定20位为S型是发挥抗癌作用的重点部位；调整A环和B环尤其是改变9、10、11位基团，可得到水溶性增大、抗癌活性强的衍生物。喜树碱已成为临床评价较高的抗癌药物。至2002年已设计合成15个新化合物，其中3个已上市，12个正处于临床阶段。作者对2002年以前有关喜树碱及其衍生物的合成及构效关系的研究情况进行综述。     

Synthesis of water-soluble (aminoalkyl)camptothecin analogues: inhibition of topoisomerase I and antitumor activity.

Water-soluble analogues of the antitumor alkaloid camptothecin (1) were prepared in which aminoalkyl groups were introduced into ring A or B. Most of the analogues were prepared by oxidation of camptothecin to 10-hydroxycamptothecin (2) followed by a Mannich reaction to give N-substituted 9-(aminomethyl)-10-hydroxycamptothecins (4-12) or by subsequent modification of Mannich product 4 (13, 15, 17, 19, 21). Others were obtained by modification of the hydroxyl group of 2 (25,26) or by total synthesis (35,42,43). These analogues, as well as some of their synthetic precursors, were evaluated for inhibition of topoisomerase I, cytotoxicity, and antitumor activity. Although there was not a quantitative correlation between these assays, compounds that inhibited topoisomerase I were also cytotoxic and demonstrated antitumor activity in vivo. Further evaluation of the most active water-soluble analogue led to the selection of 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (4, SK&F 104864) for development as an antitumor agent. In addition to its water solubility, ease of synthesis from natural camptothecin, and high potency, 4 demonstrated broad-spectrum activity in preclinical tumor models and is currently undergoing Phase I clinical trials in cancer patients.     

Structure activity relationships of synthetic antibiotic analogues of chryscandin

Anti-yeast activity with a series of chryscandin derivatives showed that the O-methyl-L-tyrosyl moiety is not always required for activity at the target site. On the other hand, the adenyl-3'-aminoribofuranuronic acid moiety seems to be essential for biological activity. Therefore, the various acyl derivatives on the amino group of the sugar part of the nucleoside were synthesized. 1-(6-Amino-9H-purin-9-yl)-3-(S-benzyl-L-cysteinylamino)- 1,3-dideoxy-beta-D-ribofuranuronic acid (16) showed the highest efficacy among them against Candida albicans. It exhibited sixteen-fold enhanced activity in vitro compared with that of native chryscandin. The in vivo activity of 16 against experimental infection of C. albicans showed the almost same as that of 5-fluorocytosine and a superior to that of ketoconazole.     

Quantitative structure activity relationships and mixture toxicity studies of alcohols and chlorohydrocarbons: Effects on growth of Daphnia magna

Effects on growth of Daphnia magna were studied for 10 non-reactive organic chemicals such as alcohols and chlorobenzenes. The ‘no observed effect concentration’ (NOEC) was very well correlated with the hydrophobicity (P_oct) of the tested compounds which appeared in a quantitative structure-activity relationship (QSAR) study. With this QSAR the NOEC for 15 other compounds was predicted. The joint toxicity of mixtures of 10 and 25 compounds was also tested. The NOEC of these mixtures was predictable on the basis of concentration-additivity.     

Diltiazem analogues: the last ten years on structure activity relationships

Cardiovascular diseases as hypertension, angina and/or supraventricular arrhythmias are among the most important death causes in the world. For the treatment of heart pathologies, calcium channel entry blockers are very important drugs, owing to their therapeutic versatility. Although few calcium antagonists described until today are structurally related to diltiazem and to the benzothiazepine class, the still high pharmaceutical interest on diltiazem analogues justifies this review. Diltiazem and its first analogues developed in the early '70s became popular in the '80s, and were pharmacologically characterized for a long time. It is in the '90s that several research groups carried out structural variations identifying novel scaffolds for diltiazem-related compounds, with significant calcium antagonist behaviour. Recently, a series of thiazino-oxadiazolone derivatives were identified as potent and selective antagonists for calcium influx into cardiac cells, and they were subsequently used to search for novel chemotypes by means of virtual screening techniques. The resulting hits could open interesting perspectives for the development of drugs to treat cardiovascular diseases. In the present review, an updated collection of diltiazem analogues is reported over the last ten years. The chemical structure and the structure activity relationships will be given, with additional mention to the potential therapeutic applications.     

Quantitative structure--activity relationships and carminative activity II: steric considerations.

The unexplained variation in the relationships between carminative activities and octanol--water distribution coefficients of various classes of compounds was explained. The steric substituent constant (Es) value, van der Waals volume, and molecular connectivity were introduced into a previously derived correlation. Each parameter brought about an improvement, and molecular connectivity was the most successful. Correlations containing molecular connectivity was the most successful. Correlations containing molecular connectivity terms explained the excess variation. The results were in agreement with a mechanism in which carminative activity depended on the availability of the oxygen atom in the functional group of the molecule and was reduced when the substituent attached to the oxygen hindered the interaction between the oxygen atom and the receptor.     

Quantitative structure–activity relationship studies of cyclooxygenase inhibitors: a comprehensive analysis

A quantitative structure‐activity relationship (QSAR) analysis of 10 structurally diverse set of compounds recently reported as cyclooxygenase (COX) inhibitors has been performed using ClogP, CMR, aromatic substituent constants, and suitable indicator variables. These revealed several important physicochemical and structural requirements for COX‐1, COX‐2 inhibitory activity, and selective inhibition of COX‐2 versus COX‐1 among these novel ligands. Seventeen QSAR models reported herein provide interesting insights in understanding the hydrophobic, steric, electronic, and structural requirements of COX inhibition among these individual set of compounds. These results may be used to further the design and development of selective COX‐2 inhibitors among these newly reported COX inhibitors. Drug Dev Res 64:220–231, 2005. © 2005 Wiley‐Liss, Inc.     

Quantitative structure -- activity relationships (QSARs) of thrombin inhibitors: review,evaluation and comparative analysis

Thrombin has become an important target for designing antithrombotic drugs in the recent years. Thus, we have undertaken a QSAR analysis aimed at individuating the physicochemical properties governing the inhibitory activity of such compounds. The QSAR equations for ten series of derivatives have been calculated and discussed. The series studied are all those that we found in the literature suitable for a QSAR study. The equations we obtained show that the main physicochemical properties affecting the inhibitory activity are almost the same for all the series and can be individuated by the use of proper parameters. The conclusions of this analysis can be summarized as follows: a). hydrophobicity plays a critical role; b). steric factors are also significant but in some cases the collinearity between steric and hydrophobic parameters does not allow one to draw any final conclusion.