JP5476650B2 - 新規dif−1誘導体 - Google Patents
新規dif−1誘導体 Download PDFInfo
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- JP5476650B2 JP5476650B2 JP2009025149A JP2009025149A JP5476650B2 JP 5476650 B2 JP5476650 B2 JP 5476650B2 JP 2009025149 A JP2009025149 A JP 2009025149A JP 2009025149 A JP2009025149 A JP 2009025149A JP 5476650 B2 JP5476650 B2 JP 5476650B2
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- dif
- cells
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- salt
- differentiation
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Description
同じく土壌微生物である「細胞性粘菌類」(胞子と柄(え)からなる粘菌子実体)と「真菌(カビ)類」は、分類学上の異なる「界(あるいは門)」に属する進化的にかけ離れた微生物群であり、本発明者らは、細胞性粘菌類を「新たな創薬資源」と考え、細胞性粘菌由来の各種薬理活性物質を単離・同定してきた。
粘菌由来の薬理活性物質の1つDIF−1(下記左)は、もともと粘菌自身の柄細胞分化を誘導する粘菌の分化誘導因子として単離された化合物である(非特許文献1)。本発明者はDIF−1やDIF−3(下記右)、さらにはそれらの誘導体が腫瘍細胞増殖阻害効果や糖代謝促進効果等の薬理活性を有することを発見し、報告した(特許文献1,2)。
しかしながら、DIF−1の側鎖にアミドを導入した化合物については合成されておらず、その生物活性も不明であった。
(1)下記一般式(I)で表わされる化合物又はその塩。
(2)R1が炭素数1〜6のアルキル基であり、R2が炭素数4〜10のアルキル基である、(1)の化合物又はその塩。
(3)R1がメチル基であり、R2が炭素数4〜8のアルキル基である、(1)の化合物又はその塩。
(4)X1およびX2が塩素である、(1)〜(3)のいずれかの化合物又はその塩。
(5)(1)の化合物であって、R1がメチル基であり、R2が炭素数4〜6のアルキル基であり、X1およびX2が塩素である化合物又はその塩を含む、細胞性粘菌分化誘導剤。
(6)(1)の化合物であって、R1がメチル基であり、R2が炭素数4〜7のアルキル基であり、X1およびX2が塩素である化合物又はその塩を含む、腫瘍細胞増殖抑制剤。
(7)(1)の化合物であって、R1がメチル基であり、R2が炭素数6〜8のアルキル基であり、X1およびX2が塩素である化合物又はその塩を含む、糖代謝促進剤。
本発明の化合物は、一般式(I)で表される。
R2は炭素数1〜10のアルキル基を示す。R2は炭素数4〜10のアルキル基であることが好ましく、炭素数4〜8のアルキル基であることがより好ましい。
なお、アルキル基は直鎖でもよいし、枝分かれを有してもよいし、環状アルキル基でもよいが、直鎖が好ましい。
X1、X2は独立してハロゲンを示し、それぞれCl、Br、Iのいずれでもよい。
一般式(I)の化合物またはその塩の医薬中の含有量は、製剤全体の約0.01ないし約100重量%である。
一般式(I)の化合物またはその塩の投与量は、投与対象、対象臓器、症状、投与方法などにより異なり特に制限されないが、一般的に、患者(体重60kgとして)に対して、一日につき約0.1〜100mg、好ましくは約1.0〜50mg、より好ましくは約1.0〜20mgである。
2,6-bis(benzyloxy)-N-butyl-4-methoxybenzamideの合成
2,6-bis(benzyloxy)-4-methoxybenzaldehyde (100 mg, 0.287 mmol) をtert-BuOH-H2O に3:1で溶解した溶液4mLに、室温で、NaH2PO4・2H2O (67 mg, 0.429 mmol), 2-methyl-2-butene (0.24 mL, 2.27 mmol) および NaClO2 (179 mg, 1.58 mmol) を連続して加えた。2時間撹拌した後、その混合物を1 M 炭酸ナトリウム水溶液 (5 mL)に加え、酢酸エチル (5 mL)で洗浄した。 水層に 1 M HClを加えて酸性にし、酢酸エチル (10 mL) で3回抽出した。有機層を食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥させ、濃縮して、粗(crude)2,6-bis(benzyloxy)-4-methoxybenzoic acidを得た。これをCH2Cl2 (3 mL)に溶解し、この溶液にn-Butylamine (80 mL, 0.81 mmol), N,N-diisopropylethylamine (150 mL, 0.86 mmol) および (125 mg, 0.328 mmol) を室温で加えた。3時間撹拌した後、そ
の混合物を0.5 M HCl (10 mL)に加え、酢酸エチル(10 mL)で3回抽出した。有機層をH2O および食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥させ、濃縮した。得られた残渣についてシリカゲルクロマトグラフィーを行い、CHCl3-MeOH (49:1) で溶出し、2,6-bis(benzyloxy)-N-butyl-4-methoxybenzamideを得た [96 mg, 0.23 mmol (収率 76 % )]。 他の誘導体は、n-butylamineの代わりに対応するアミンを用いる以外は同様にして合成した。
上記2,6-Bis(benzyloxy)-N-butyl-4-methoxybenzamide (96 mg, 0.23 mmol) と、炭素(30 mg) に付着させた20% Pd(OH)2 をMeOH (5.0 mL) に加え、室温、水素雰囲気下で1時間撹拌した。濾過後、濾液を濃縮して、粗(crude)N-butyl-2,6-dihydroxy-4-methoxybenzamideを得た。これをCHCl3 (3 mL) に溶解し、得られた溶液にsulfuryl chloride (62 mg, 0.46 mmol) とEtOH (60 mL) を室温で加えた。20分間撹拌した後、混合物を濃縮した。得られた残渣についてシリカゲルクロマトグラフィーを行い、CHCl3-MeOH (9:1) で溶出を行い、N-butyl-3,5-dichloro-2,6-dihydroxy-4-methoxybenzamide (DIF-1[A]) [22 mg,
0.071 mmol (収率 31% )]を得た。
黄色無定形固体; 1H NMR (400 MHz, CDCl3) d 10.88 (2H, br.s), 8.19 (1H, br.s), 3.94 (3H, s), 3.43-3.48 (2H, m), 1.57-1.64 (2H, m), 1.37-1.46 (2H, m), 0.96 (3H, t,
J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) d 168.6, 155.6 (2C), 154.4 107.6, 100.5 (2C), 60.9, 39.4, 31.2, 20.1, 13.7; HREIMS m/z 307.0356 [M]+ (化学式C12H15NO4 35Cl2で計算すると307.0378).
DIF-1[A+1]: 無色無定形固体; HREIMS m/z 321.0514 [M]+ (化学式C13H17NO4 35Cl2で計算すると321.0535).
DIF-1[A+2]: 無色無定形固体; HREIMS m/z 335.0689 [M]+ (化学式C14H19NO4 35Cl2で計算すると335.0691).
DIF-1[A+3]: 無色無定形固体; HREIMS m/z 349.0835 [M]+ (化学式C15H21NO4 35Cl2で計算すると349.0848).
DIF-1[A+4]: 無色無定形固体; HREIMS m/z 363.0991 [M]+ (化学式C16H23NO4 35Cl2で計算すると363.1004).
細胞性粘菌の未分化細胞(アメーバ状)は、適当なin vitro条件下で培養すると、細胞が分泌するDIF-1の作用で柄細胞(細胞壁を有する細胞:位相差顕微鏡観察で簡単に同定できる)に分化する。ところが、DIF-1を合成できない変異株HM44細胞は、同様の条件下で培養しても柄細胞に分化できない。しかし、この株に培地中にDIF-1を補ってやると、DIF-1の濃度に応じた数の細胞が柄細胞に分化する(特開2006-340615号公報)。
このHM44のin vitro culture系を利用して、外から加えた化合物に柄細胞分化誘導能があるか否かを検定した。分化した柄細胞は、位相差顕微鏡観察によって判別し、分化比率に基づいて分化誘導活性を定量化した。
未分化HM44細胞をバクテリアKlebsiella aerogenesと共に寒天培地(4.4 g KH2PO4, 2 g Na2HPO4, 1 g MgSO4・7H2O, 7.5 g glucose, 10 g Bacto-peptone, 1 g Yeast extract, 15 g agarを1 literの水に溶かし加熱後、agarを固めた培地)上で、21℃インキュベーター内にて培養、増殖させた。なお、Klebsiella aerogenesは粘菌の餌として加えた。
次に、増殖した粘菌細胞を塩溶液(10 mM NaCl, 10 mM KCl:以下BSSと呼ぶ)で集め、遠心分離(1500〜2500 rpm)によってバクテリアと分離し、BSSを加え何度か洗浄した。集めた細胞を2×105 cells/wellの細胞密度で12-well plateに播き、試験化合物 0.5 nM を含む0.5 mL/wellの塩溶液(5 mM cAMP, 2 mM NaCl, 10 mM KCl, 1 mM CaCl2, 200 μg/ml streptomycin sulfate, 10 mM MES-KOH, pH 6.2)で、21℃で48時間培養した。
培養後、分化した柄細胞を位相差顕微鏡にて観察し、分化比率を算出した。
結果を図1Aに示した。その結果、それぞれ0.5nMのDIF-1[A+1]とDIF-1[A+2]が、DIF-1とほぼ同程度の分化誘導活性を示し、DIF-1[A]もDIF-1の約60%の分化誘導活性を示した。
そこで、図1Bにおいて、DIF-1, DIF-1[A+1], DIF-1[A+2]の分化誘導能について詳細な検討を行い、それぞれのED50が、0.45 nM, 0.35 nM, 0.3 nMであることがわかった。
これらの結果から、DIF-1[A+1]とDIF-1[A+2]がDIF-1のagonistsとして利用できることが示唆された。
ヒト白血病細胞株であるK562細胞(2×104細胞/ml)を12穴プレートに1mlずつ分注し、そこに、15 μM DIF誘導体を加えて、3日間培養した後、細胞数を比較した
。細胞数はこの化合物を加えない場合に対する相対値(%)で示した(図2A)。図2(B)では、DIF-1, DIF-1[A], DIF-1[A+1], DIF-1[A+2]、DIF-1[A+3]について濃度を変えて詳細な検討を行った。以上より、これらの化合物がK562細胞の増殖を強く抑制することがわかった。これらの結果は、DIF-1のamide誘導体が抗白血病薬として利用できる可能性を示唆している。
正常細胞のモデルとして、増殖期の3T3-L1細胞を、15 μM DIF誘導体存在下で3日間in
vitro培養し、細胞数を比較した。
その結果、ほとんどのDIF誘導体はこの細胞の増殖をあまり抑制しなかった(図3A)。これらの結果は、DIF誘導体を抗白血病薬として使用した際に懸念される副作用(正常細胞の増殖阻害)が比較的小さいことを期待させる。
マウス3T3-L1繊維芽細胞を適当な培地1ml中(12穴のプラスチック容器中)でコンフルエント状態になるまで数日間培養した。次に、DIF-1誘導体の溶剤である0.2%エタノールのみを加えた栄養培地(EtOH)、20 μM DIF誘導体を加えた栄養培地で、それぞれ数時間培養し、培地中のブドウ糖の濃度を測定し、それぞれの細胞の糖代謝の速度を計算し、コントロールに対する比で表した(図3B)。その結果、DIF-1だけでなく、DIF-1[A+2]、DIF-1[A+3]、DIF-1[A+4]の存在下で、細胞の糖代謝速度が上がることが明らかとなった。これらの結果は、DIF-1のamide誘導体も糖尿病や肥満治療薬のリード化合物となる可能性を示している。
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