Synthesis and antitumor activity of spergualin analogues. I. Chemical modification of 7-guanidino-3-hydroxyacyl moiety

Many analogues and derivatives of an antitumor antibiotic, spergualin, were synthesized, and the relationships between the structure and the activity against mouse L-1210 tumor were studied. Both modification of the 15-hydroxyl group and alteration of chain-length of the omega-guanidinoacyl moiety affected the activity. 15-Deoxyspergualin (18, 1-amino-19-guanidino-11-hydroxy-4,9,12-triazanonadecane-10,13-d ion e) and its analogue 25 (1-amino-21-guanidino-11-hydroxy-4,9,12-triazauneicosane-10,13-dio ne) had strong activity, superior to that of spergualin.     

Immunosuppressive activity of 15-deoxyspergualin and its effect on skin allografts in rats

The immunosuppressive activity of spergualin analogues, 15-deoxyspergualin and N-30, is presented. These compounds suppressed antibody formation and establishment of delayed-type hypersensitivity to sheep red blood cells (SRBC) in mice. Among spergualin, 15-deoxyspergualin, and N-30, 15-deoxyspergualin was most effective in suppressing immune responses. It suppressed antibody formation against SRBC by spleen cell cultures in a dose-dependent fashion without reducing cell viability. The spergualins also suppressed the mixed lymphocyte culture reaction. Peritoneal exudate cells taken from mice given immunosuppressive doses of 15-deoxyspergualin were not reduced in their functions measured: Release of lysosomal enzymes and production of superoxide anions. 15-Deoxyspergualin and N-30 were markedly effective in prolonging skin graft in rats.     

Synthesis of (-)-15-deoxyspergualin and (-)-spergualin-15-phosphate

The method for chemical modification of spergualin with retention of the configuration at the C-11 has been achieved by the use of tetrahydropyranyl group for protection of the 11-hydroxyl group. (-)-15-Deoxyspergualin (2), which shows about eight times stronger inhibition against mouse leukemia L-1210 than the natural (-)-spergualin(1), and (-)-spergualin-15-phosphate(3) possessing a good antitumor activity have been synthesized starting from 1.     

Synthesis and antitumor activity of tropolone derivatives. 2

Structural requirement for antitumor activity of tropolone derivatives 2-4 was explored. Isochroman derivatives (6-17, 20, and 23) and alpha, alpha-disubstituted compounds 26-30 were synthesized and their antitumor activities were tested. These nontroponoid derivatives were all inactive, implying that a tropolone ring is essential for the activity. Several compounds related to the monotropolone analogue 3 were synthesized. Among them, 31-33 showed significant activity, but their potencies were considerably weaker than those of binary tropolone analogues 4.     

Adenosine deaminase inhibitors. Synthesis and biological activity of deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine

Two new deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, 1), 7-deaza-EHNA (6) and 1,3-dideaza-EHNA (11), were synthesized and evaluated for adenosine deaminase (ADA) inhibitory activity and compared with EHNA, 1-deaza-EHNA (2), and 3-deaza-EHNA (3). Substitution of a methine group for a nitrogen atom in the 7-position of the purine moiety of EHNA produces a dramatic drop in the inhibitory activity (Ki = 4 X 10(-4) M) whereas compounds 2 and 3 are still good inhibitors (Ki = 1.2 X 10(-7) M and 6.3 X 10(-9) M respectively). EHNA and its deaza analogues so far synthesized were also tested in vitro for their antiviral and antitumor activity in a range of cellular systems. EHNA and 1-deaza-EHNA are equiactive as inhibitors of human respiratory syncytial virus (HRSV) replication (MIC = 6.25 micrograms/mL) while the other compounds are inactive. On the other hand, all the examined compounds displayed an antitumor activity comparable to that of the reference compound 1-beta-D-arabinofuranosyladenine (ara-A), 7-deaza-EHNA being the most active of all. The results obtained showed that there is no correlation between adenosine deaminase inhibition and antiviral or antitumor activity in this series of compounds. 3-Deaza-EHNA, the most active inhibitor of ADA among the EHNA deaza analogues, greatly potentiates the antitumor activity of ara-A in vitro. In vivo activity was observed only when the two compounds were used in combination.     

Synthesis and antitumor activity of a series of lactone-opened camptothecin derivatives

A series of E-ring lactone-opened camptothecin (CPT) derivatives bearing with terminal aza-heterocyclic groups were synthesized, and their antitumor activity was evaluated both in vitro and in vivo. Hydroxyl-amide analogues with morpholin-4-yl displayed excellent antitumor activity in vitro and efficient inhibition on tumor xenograph model in nude mice. Ester-amide compounds acted less active in vitro cytotoxicity and lower inhibition activity in vivo. Substitutions at 7- and 10- positions favored the antitumor activity.     

Synthesis and antitumor activity of halogen-substituted 4-(3,3-dimethyl-1-triazeno)quinolines

Halogenated 4-(3,3-dimethyl-1-triazeno)quinolines were synthesized as potential antitumor agents on the basis of the biochemical pharmacological properties of existing triazenes, their structural-activity relationships, and the high melanin binding of chloroquine and iodoquine in vivo and in vitro. They were synthesized by diazotization of appropriate halogen-substituted 4-aminoquinolines in fluoboric acid at -5 degrees C followed by coupling with dimethylamine. Among these new compounds, 8-chloro-4-(3,3-dimethyl-1-triazeno)quinoline produces significant antitumor activity against both P-388 and L1210 murine leukemias. Although only marginally active or inactive against P-388, the other chloro, bromo, or iodo analogues show activity against L1210 comparable to that of dacarbazine (DIC). However, none of these compounds is active against B-16 melanoma. Compared with DIC these new agents demonstrate a higher in vitro affinity for melanin; however, this affinity is apparently not correlated with their antitumor activity.     

Synthesis and antitumor activity of spergualin analogues. II. Chemical modification of the spermidine moiety

Chemical modifications of the spermidine moiety of an antitumor antibiotic, spergualin (Ia), and the structure-activity relationship are described. Replacement of spermidine with other polyamines decreased the antitumor activity against mouse leukemia L1210. Analogues containing an oxidized spermidine moiety that probably formed during oxidation with amine oxidase were inactive. Spermidine is indispensable for the antitumor activity. A facile method for the synthesis of glyoxyloyl polyamine, a key intermediate of spergualin-related compounds, is also reported.     

Synthesis of β-hydroxy-propenamide derivatives and the inhibition of human dihydroorotate dehydrogenase

Novel beta-hydroxy propenamides as analogues of the active metabolite of leflunomide (A 771726) were synthesized and evaluated for their inhibitory activity on dihydroorotate dehydrogenase (DHODH) in an investigation into their immunosuppressive activity. Compounds 2a, 3a, and 3h were approximately 4-40 times more potent than leflunomide in their activity while they were-less active than A 771726.     

Synthesis and antitumor activity of several new analogues of penclomedine and its metabolites

Analogues of penclomedine (PEN, 3,5-dichloro-4,6-dimethoxy-2-(trichloromethyl)pyridine) and its metabolites have been synthesized and evaluated as potential antitumor agents. PEN and 4-DMPEN (3,5-dichloro-4-hydroxy-6-methoxy2-(trichloromethyl)pyridine (3a)), the major plasma metabolite in patients, were modified at 4- and 6-positions with different alkyl, aryl, and ester groups. All of the analogues and many of the intermediates were evaluated against the PEN-sensitive MX-1 human breast tumor xenograft in vivo, and several analogues of PEN and 4-DMPEN showed modest to curative activity.     

Antitumor activity of 2(S)-5,2′,5′-trihydroxy-7,8-dimethoxyflavanone and its analogues

In an effort to increase of the antitumor activity of 2(S)-5,2',5'-trihydroxy-7,8-dimethoxyflavanone isolated fromScutellaria indica, we synthesized its analogues,II, III, andIV. They showed potent cytotoxicityin vitro against cancer cell lines, L1210, K562 and A549. On the basis of ED(50) values against the cancer cell lines,III exhibited about 2-7 times stronger activity thanI against various cell lines. We tested the antitumor activity of the analogues against Sarcoma 180 cellsin vivo and evaluated the structure-activity relationship. The antitumor activity appeared to be related to the hydrogen bond between carbonyl group at C-4 and hydroxyl group at C-5, in contrast to cytotoxic action.     

Synthesis and bioevaluation of novel analogues of justicidin A

Nine analogues of natural lignan justicidin A were easily synthesized employing Williamson etherification in yields of 76–84%. Compounds were evaluated for their cytotoxic activities against hepatocellular carcinoma (HepG2) cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. All synthesized analogues showed better antitumor activity than etoposide.     

4-(2-酰胺基-2-乙氧羰基)乙硫基-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成与抗肿瘤活性

为考察4′-去甲基表鬼臼毒素4位上取代基结构变化与抗肿瘤活性的关系,设计并合成了23个标题化合物。体外L_(1210)白血病细胞与KB细胞生长抑制试验的结果表明,化合物11,16和18的抗肿瘤活性超过依托泊甙,化合物8的活性与依托泊甙相当。     

1,2-bis(arylsulfonyl)hydrazines. 2. The influence of arylsulfonyl and aralkylsulfonyl substituents on antitumor and alkylating activity

Several 1,2-bis(arylsulfonyl)-1-methylhydrazines were synthesized and evaluated for antineoplastic activity against the L1210 leukemia. The most active compound to emerge from this study, 2-[(4-chlorophenyl)sulfonyl]-1-methyl-1-(4-tolylsulfonyl)hydrazine , increased the survival time of tumor-bearing mice by 88%. The alkylating activity of the synthesized analogues and several compounds reported earlier was determined by measuring the absorbance at 540 nm of the alkylated product of 4-(4-nitrobenzyl)pyridine. The results obtained support the concept that the ability to alkylate is a necessary but not a sufficient condition for the expression of antitumor activity by agents of this class.     

4-酰硫基-4-脱氧-4-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性

为研究4’-去甲表鬼臼毒素的C₄位不同原子及不同取代基类型同活性之间的关系,寻找活性高、毒性低的抗肿瘤新药,合成了11个4-酰硫基-4-脱氧-4’-去甲表鬼臼毒素,衍生物并进行了抗肿瘤活性试验。4-巯基-4-脱氧-4’-去甲表鬼臼毒素和不同的羧酸在二乙氧基磷酰氰酯存在下得相应的硫酯。该类化合物在L1210白血病细胞和KB细胞的体外抑制试验中普遍表现出抑制活性。化合物10的活性与依托泊甙相当。其余活性比依托泊甙差。与相应的C₄位酰氨基的4’-去甲表鬼臼毒素衍生物相比,活性明显弱。提示氮取代的衍生物活性更好。     

Synthesis and biological evaluation of new amino acids structurally related to the antitumor agent acivicin

A set of racemic conformationally constrained analogues of the antitumor antibiotic acivicin (+)-1 has been prepared through a strategy based on 1,3-dipolar cycloaddition of bromonitrile oxide to suitable dipolarophiles. The bromo analogue (2) of acivicin was also synthesized and tested as a reference compound, together with its stereoisomer 3. The antitumor properties of novel amino acids 4-7 were evaluated in vitro against human tumor cell lines. Their efficacy to inhibit glutamate synthase (GltS) from Azospirillum brasilense was also assayed. None of the studied compounds, but 2, showed significant activity.     

Synthesis and antineoplastic evaluations of 5,8-bis[(aminoalkyl)amino]-1-azaanthracene-9,10-diones

Several 5,8-bis[(aminoalkyl)amino]-1-azaanthracene-9,10-diones have been synthesized and evaluated for antitumor activity against L1210 leukemia both in vitro and in vivo. Comparisons are made to the corresponding carbocyclic analogues. One of the aza analogues showed modest in vivo activity.     

Combretastatins类肿瘤血管阻断剂的构效关系研究

目的:通过对Combretastatins类肿瘤血管阻断剂构效关系研究,筛选出有潜力成为新一代肿瘤血管阻断剂候选药物。方法:以CA4为先导化合物,合成了6个全新的CA4类似物,并对其进行体外抗肿瘤实验以及酶抑制的活性测试研究。结果:6个全新化合物具有不同程度的抑制人癌细胞株增殖的作用,其中以C002化合物体外抗肿瘤活性最强。结论:化合物C002体外抗肿瘤活性与CA4相当,有潜力成为新一代肿瘤血管阻断剂的候选药物。     

Synthesis and antitumor activity of duocarmycin derivatives: modification of segment-A of A-ring pyrrole compounds.

A series of 3-substituted A-ring pyrrole compounds of duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S(3) cells and in vivo antitumor activity against murine sarcoma 180 in mice. These compounds were evaluated on the peripheral blood toxicity and delayed lethal toxicity. Further, to expand our investigation of their peripheral blood toxicity, the toxicity to bone marrow cells (CFU-GM, CFU-Meg) was investigated. Among 3-substituted A-ring pyrrole compounds of duocarmycin bearing a 5',6',7'-trimethoxy-2'-indolecarboxyl group as segment-B (Seg-B), several analogues showed remarkably potent antitumor activity with low peripheral blood toxicity. The 3-formyl compound 12h, one of such analogues, showed stronger antitumor activity with lower toxicity to bone marrow cells compared to DU-86 (2a), an active metabolite of KW-2189 (2b). However, compound 12h caused delayed death. On the other hand, the 3-bromo compound 15f, one of the 3-substituted A-ring pyrrole derivatives bearing a 4'-methoxycinnamoyl group as Seg-B, showed the most potent antitumor activity among the 4'-methoxycinnamate analogues with low toxicity to bone marrow cells. Furthermore, compound 15f did not cause delayed death similarly to 2d. These results would indicate the importance of the C-3 substituents of A-ring pyrrole duocarmycin derivatives for exhibiting antitumor activity and decreasing toxicity.     

4-O-卤代酰基-4′-去甲基表鬼臼毒素类似物的合成与抗肿瘤活性

为考察4′-去甲表鬼臼毒素C₄位上联结含卤素原子的酯化侧链时对化合物抗肿瘤活性的影响,设计并采用选择性酯化方法合成了9个新的4′-去甲基表鬼臼毒素酯化产物。其中标题化合物在L₁₂₁₀白血病肿瘤细胞与KB细胞的体外生长抑制试验中普遍表现出显著的抑制活性,大部分化合物活性超过依托泊甙。而普通脂酸酯的活性较弱。